Cot modulators and methods of use thereof

ABSTRACT

The present disclosure relates generally to modulators of Cot (cancer Osaka thyroid) and methods of use and manufacture thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/861,390 filed on Jun. 14, 2019, the entire content of which is herebyincorporated by reference in its entirety.

FIELD

The present disclosure relates generally to modulators of Cot (cancerOsaka thyroid) and methods of use and manufacture thereof.

BACKGROUND

Cot (cancer Osaka thyroid) protein is a serine/threonine kinase that isa member of the MAP kinase kinase kinase (MAP3K) family. It is alsoknown as “TPL2” (tumor progression locus), “MAP3K8” (mitogen-activatedprotein kinase kinase kinase 8) or “EST” (Ewing sarcoma transformant).Cot was identified by its oncogenic transforming activity in cells andhas been shown to regulate oncogenic and inflammatory pathways.

Cot is known to be upstream in the MEK-ERK pathway and is essential forLPS induced tumor necrosis factor-α (TNF-α) production. Cot has beenshown to be involved in both production and signaling of TNFα. TNFα is apro-inflammatory cytokine and plays an important role in inflammatorydiseases, such as rheumatoid arthritis (RA), multiple sclerosis (MS),inflammatory bowel disease (IBD), diabetes, sepsis, psoriasis,misregulated TNFα expression and graft rejection.

Agents and methods that modulate the expression or activity of Cot,therefore, may be useful for preventing or treating such diseases.

SUMMARY

The present disclosure provides compounds that modulate the expressionor activity of Cot. The disclosure also provides compositions, includingpharmaceutical compositions, kits that include the compounds, andmethods of using (or administering) and making the compounds. Thecompounds provided herein can be useful in treating diseases, disorders,or conditions that are mediated by Cot. The disclosure also providescompounds for use in therapy. The disclosure further provides compoundsfor use in a method of treating a disease, disorder, or condition thatis mediated by Cot. Moreover, the disclosure provides uses of compoundsin the manufacture of a medicament for the treatment of a disease,disorder or condition that is mediated by (or mediated, at least inpart, by) Cot.

In one aspect, provided is a compound having structure of Formula I:

whereinR¹ is hydrogen, —O—R⁷, —N(R⁸)(R⁹), —C(O)—R⁷, —S(O)₂—R⁷, —C₁₋₉ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, orheteroaryl;

-   -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally        substituted with one to four Z¹;        R² is hydrogen, —C(O)—R⁷, —C(O)O—R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z²;        or R¹ and R² together with the nitrogen to which they are        attached to form a heterocyclyl or heteroaryl, wherein each        heterocyclyl or heteroaryl is optionally substituted with one to        four Z²;        R³ is heterocyclyl or heteroaryl, wherein each heterocyclyl or        heteroaryl is optionally substituted with one to four Z³;        R⁴ is aryl, heterocyclyl or heteroaryl, wherein each aryl,        heterocyclyl, or heteroaryl is optionally substituted with one        to four Z⁴;        R⁵ is hydrogen, halo, —CN, —NO₂, —O—R⁷, —N(R⁸)(R⁹), —S(O)—R⁷,        —S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷,        —OC(O)O—R⁷, —OC(O)N(R¹⁰)(R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉        alkylthio, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl,        and heteroaryl may be optionally substituted with one to four        Z⁵;        R⁶ is —C(O)O—R¹⁶—OP(O)(OR¹²)₂—C(O)—R¹⁶—OP(O)(OR¹²)₂,        —R¹⁶—OP(O)(OR¹²)₂, —C(O)O—R¹⁶—OR¹⁷; —C(O)O—R¹⁶—OH;        —C(O)O—R¹⁶—OC(O)R¹⁷; —C(O)—C(O)OR¹², or —C(O)O—R¹⁶—OC(O)R¹⁷NH₂;        each R⁷ is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,        heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z⁷;        R⁸ and R⁹ at each occurrence are independently hydrogen,        —S(O)₂R^(m), —C(O)—R^(m), —C(O)O—R¹⁰, —C(O)N(R¹⁰)(R¹¹), C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅        cycloalkyl, aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl        may be optionally substituted with one to four Z⁸;        R¹⁰ and R¹¹ at each occurrence are independently hydrogen, C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅        cycloalkyl, aryl, heterocyclyl, or heteroaryl,    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        optionally is substituted with one to four Z^(1b);        each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, and Z⁸ is independently        hydrogen, oxo, halo, —NO₂, —N₃, —CN, thioxo, C₁₋₉ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl,        heteroaryl, heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹²,        —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,        —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹³)(R¹⁴),        —N(R¹²)S(O)₂(R¹²), —NR¹²S(O)₂N(R¹³)(R¹⁴), —NR¹²S(O)₂O(R¹²),        —OC(O)R², —OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂, —OP(O)(OR¹²)₂,        —CH₂P(O)(OR²)₂, —OCH₂P(O)(OR¹²)₂, —C(O)OCH₂P(O)(OR¹²)₂,        —P(O)(R²)(OR¹²), —OP(O)(R²)(OR¹²), —CH₂P(O)(R¹²)(OR²).        —OCH₂P(O)(R¹²)(OR¹²), —C(O)OCH₂P(O)(R²)(OR¹²), —P(O)(N(R¹²)₂)₂,        —OP(O)(N(R¹²)₂)₂, —CH₂P(O)(N(R²)₂)₂, —OCH₂P(O)(N(R²)₂,        —C(O)OCH₂P(O)(N(R²)₂, —P(O)(N(R²)₂)(OR²), —OP(O)(N(R²)₂)(OR¹²),        —CH₂P(O)(N(R¹²)₂)(OR¹²), —OCH₂P(O)(N(R¹²)₂)(OR¹²),        —C(O)OCH₂P(O)(N(R²)₂)(OR¹²). —P(O)(R²)(N(R¹²)₂),        —OP(O)(R²)(N(R¹²)₂), —CH₂P(O)(R¹²)(N(R¹²)₂),        —OCH₂P(O)(R²)(N(R²)₂), —C(O)OCH₂P(O)(R¹²)(N(R¹²)₂). —Si(R¹²)₃,        —S—R², —S(O)R², —S(O)(NH)R², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl,        aryl, heteroaryl or heterocyclyl is optionally substituted with        one to four Z^(1a) groups;        each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈        haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹²,        —C(O)O—R², —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R³)₂(R¹⁴)⁺,        —N(R¹²)—C(O)R², —N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹³)(R¹⁴),        —N(R¹²)S(O)₂(R¹²), —N(R¹²)S(O)₂—N(R¹³)(R¹⁴), —N(R²)S(O)₂O(R²),        —OC(O)R¹², —OC(O)OR², —OC(O)—N(R¹³)(R¹⁴), —Si(R¹²)₃, —S—R²,        —S(O)R², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        each R¹² is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or        heterocyclyl,    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(ib) groups;        R¹³ and R¹⁴ at each occurrence are each independently hydrogen,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl,        heteroaryl or heterocyclyl;    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups, or R¹³ and R¹⁴ together with the nitrogen to        which they are attached form a heterocyclyl, wherein said        heterocyclyl is optionally substituted with one to four Z^(1b)        groups;        each R¹ is independently halo, —CN, —NO₂, —O—R⁷, —N(R⁸)(R⁹),        —S(O)—R⁷, —S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷,        —OC(O)O—R⁷, —OC(O)N(R¹⁰)(R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl;        R¹⁶ is —C₁₋₃ alkyl or cyclopropyl optionally substituted with        one to four C₁₋₃ alkyl or cyclopropyl;        R¹⁷ is C₁₋₉ alkyl, cycloalkyl, or heterocyclyl optionally        substituted with one to three R⁶;        and        each Z¹, Z², Z⁴, Z⁵, Z⁷, and Z is independently hydrogen, oxo,        halo, —NO₂, —N₃, —CN, thioxo, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl,        heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹³)(R¹⁴),        —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹²,        —N(R¹²)C(O)N(R¹³)(R¹⁴), —N(R¹²)S(O)₂(R¹²), —NR²S(O)₂N(R¹³)(R¹⁴),        —NR²S(O)₂O(R²), —OC(O)R², —OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂,        —OP(O)(OR¹²)₂, —CH₂P(O)(OR¹²)₂. —OCH₂P(O)(OR¹²)₂,        —C(O)OCH₂P(O)(OR¹²)₂, —P(O)(R²)(OR¹²), —OP(O)(R²)(OR¹²),        —CH₂P(O)(R²)(OR¹²), —OCH₂P(O)(R¹²)(OR¹²),        —C(O)OCH₂P(O)(R²)(OR¹²), —P(O)(N(R¹²)₂, —OP(O)(N(R¹²)₂)₂,        —CH₂P(O)(N(R²)₂, —OCH₂P(O)(N(R²)₂, —C(O)OCH₂P(O)(N(R²)₂,        —P(O)(N(R¹²)₂)(OR¹²), —OP(O)(N(R¹²)₂)(OR²),        —CH₂P(O)(N(R¹²)₂)(OR¹²). —OCH₂P(O)(N(R¹²)₂)(OR²),        —C(O)OCH₂P(O)(N(R¹²)₂)(OR¹²), —P(O)(R²)(N(R¹²)₂),        —OP(O)(R²)(N(R¹²)₂), —CH₂P(O)(R¹²)(N(R¹²)₂),        —OCH₂P(O)(R¹²)(N(R¹²)₂), —C(O)OCH₂P(O)(R¹²)(N(R¹²)₂), —Si(R¹²)₃,        —S—R², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl,        aryl, heteroaryl or heterocyclyl is optionally substituted with        one to four Z_(1a) groups;        Z⁹ is hydrogen, halo, —CN, or —O—R¹²;        each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈        haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R², —C(O)R²,        —C(O)O—R², —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R³)₂(R¹⁴)⁺,        —N(R¹²)—C(O)R², —N(R¹²)C(O)O(R²), —N(R¹²)C(O)N(R¹³)(R¹⁴),        —N(R²)S(O)₂(R¹²), —N(R²)S(O)₂—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂O(R¹²),        —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹³)(R¹⁴), —Si(R¹²)₃, —S—R¹²,        —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴); wherein        any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or        heterocyclyl is optionally substituted with one to four Z^(1b)        groups;        each Z^(1b) is independently oxo, thioxo, hydroxy, halo, —NO₂,        —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl,        —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅        cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl), —O(heteroaryl),        —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl),        —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl),        —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂,        —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅ cycloalkyl)₂,        —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,        —N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₂₋₆ alkenyl), —N(C₁₋₉        alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉        alkyl)(C₁₋₈ haloalkyl), —N(C₁₋₉ alkyl)(aryl), —N(C₁₋₉        alkyl)(heteroaryl), —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁-9        alkyl), —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅        cycloalkyl), —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl),        —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl),        —C(O)O(C₂₋₆ alkenyl), —C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅        cycloalkyl), —C(O)O(C₁₋₈ haloalkyl), —C(O)O(aryl),        —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂, —C(O)NH(C₁₋₉        alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),        —C(O)NH(C₃₋₁₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl),        —C(O)NH(aryl), —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl),        —C(O)N(C₁₋₉ alkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆        alkynyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂,        —C(O)N(aryl)₂, —C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂,        —NHC(O)(C₁₋₉ alkyl), —NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆        alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl), —NHC(O)O(C₂₋₆        alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl),        —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl),        —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl), —NHC(O)NH(C₂₋₆        alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈        haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),        —NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl), —S(C₂₋₆ alkenyl),        —S(C₂₋₆ alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈ haloalkyl),        —S(aryl), —S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl),        —N(C₁₋₉ alkyl)S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆        alkynyl), —S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁₋₈ haloalkyl),        —S(O)(aryl), —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉        alkyl), —S(O)₂(C₂₋₆ alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        or —S(O)₂N(C₁₋₉ alkyl)₂;    -   wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl        is optionally substituted with one to four halo, C₁₋₉ alkyl,        C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉ alkyl), —NH(C₃₋₁₅        cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl), —NH(heteroaryl),        —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅ cycloalkyl)₂,        —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅        cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl),        —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),        —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl);        m is 0, 1, or 2;

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof. Some embodiments provide amethod of using (or administering) the compounds of Formula I, oradditional Formula(s) described throughout, in the treatment of adisease or condition in a mammal, such as a human, that is amenable totreatment by a Cot modulator.

In certain embodiments, the disclosure provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof the disclosure (e.g. a compound of Formula I or additional Formula(s)described throughout), and at least one pharmaceutically acceptableexcipient.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 depicts plasma concentration over time of Compound A followingoral administration of Compound B to dogs compared to oraladministration of Compound A over time.

FIG. 2 depicts plasma concentration over time of Compound A and CompoundD following oral administration of Compound C to dogs over time.

DETAILED DESCRIPTION

The present disclosure relates to inhibitors of Cot, or TPL2. Thedisclosure also relates to compositions and methods relating toinhibitors of TPL2 and the use of such compounds for treatment andprophylaxis of diseases and conditions through binding of TPL2 with saidcompounds. The disclosure also relates to compositions and methods fortreating and preventing cancer, diabetes, inflammatory disease, or liverdisease including a TPL2 inhibitor in combination with one or moreadditional therapeutic agents.

A number of Cot inhibitors are known and are being investigated inconnection with a number of physiological conditions, including forexample inflammatory diseases. Cot, or TPL2, has been shown to regulateoncogenic and inflammatory pathways. TPL2 was identified by itsoncogenic transforming activity in cells and has been shown to regulateoncogenic and inflammatory pathways. TPL2 is expressed in a broad rangeof immune cells and regulates ERK-mediated gene expression downstream ofmultiple stimuli, including for example bacterial products, such as LPSand bacterial peptidoglycans, TNFα, and IL-1β. In inflammatory boweldisease, for instance, intestinal inflammation reflects the loss of ahomeostatic relationship between intestinal microbiota and the hostimmune system. In IBD, the homeostatic response to commensal bacteriacan be replaced by sustained and exacerbated immune signaline. TPL2inhibition can provide an opportunity to restor immune homeostasis, forexample, in IBD patients by attenuating exacerbated inflammatorysignaling.

Embodiments of the present disclosure provide compounds that provideinhibition of TPL2. In some embodiments, compounds disclosed hereinexhibit desirable pharmacokinetic properties. In some embodiments,compounds disclosed herein are cleaved, for exampleintestinally-cleaved, to provide compounds that inhibit TPL2. In someembodiments, compounds disclosed herein have improved solubility incomparision with known inhibitors of TPL2. In some embodiments,compounds disclosed herein provide improved systemic exposure of TPL2inhibitors relative to known compounds.

Definitions and Genera/Parameters

The following description sets forth exemplary methods, parameters andthe like. It should be recognized, however, that such description is notintended as a limitation on the scope of the present disclosure but isinstead provided as a description of exemplary embodiments.

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash that is not between two letters or symbols is used to indicate apoint of attachment for a substituent. For example, —C(O)NH₂ is attachedthrough the carbon atom. A dash at the front or end of a chemical groupis a matter of convenience; chemical groups may be depicted with orwithout one or more dashes without losing their ordinary meaning. A wavyline drawn through a line in a structure indicates a point of attachmentof a group. Unless chemically or structurally required, nodirectionality is indicated or implied by the order in which a chemicalgroup is written or named.

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms. Reference to “about” a value or parameterherein includes (and describes) embodiments that are directed to thatvalue or parameter per se. In certain embodiments, the term “about”includes the indicated amount ±10%. In other embodiments, the term“about” includes the indicated amount ±5%. In certain other embodiments,the term “about” includes the indicated amount ±1%. Also, to the term“about X” includes description of “X”. Also, the singular forms “a” and“the” include plural references unless the context clearly dictatesotherwise. Thus, e.g., reference to “the compound” includes a pluralityof such compounds and reference to “the assay” includes reference to oneor more assays and equivalents thereof known to those skilled in theart.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆alkyl), or 1 to 4 carbon atoms (i.e., CM alkyl). Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having aspecific number of carbons is named by chemical name or identified bymolecular formula, all positional isomers having that number of carbonsmay be encompassed; thus, for example, “butyl” includes n-butyl (i.e.—(CH₂)₃CH₃). sec-butyl (i.e. —CH(CH₃)CH₂CH₃), isobutyl (i.e.—CH₂CH(CH₃)₂) and tert-butyl (i.e. —C(CH₃)₃); and “propyl” includesn-propyl (i.e. —(CH₂)₂CH₃) and isopropyl (i.e. —CH(CH₃)₂).

“Alkenyl” refers to an alkyl group containing at least one carbon-carbondouble bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkenyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., CM alkenyl). Examples ofalkenyl groups include ethenyl, propenyl, butadienyl (including1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an alkyl group containing at least one carbon-carbontriple bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkynyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl). The term“alkynyl” also includes those groups having one triple bond and onedouble bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

“Haloalkoxy” refers to an alkoxy group as defined above, wherein one ormore hydrogen atoms are replaced by a halogen.

“Alkylthio” refers to the group “alkyl-S—”.

“Acyl” refers to a group —C(O)R, wherein R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein. Examples of acylinclude formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl,and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(O)NR^(y)R^(z) and an “N-amido” group which refers to the group—NR^(y)C(O)R^(z), wherein R^(y) and R^(z) are independently selectedfrom the group consisting of hydrogen, alkyl, aryl, haloalkyl, orheteroaryl; each of which may be optionally substituted.

“Amino” refers to the group —NR^(y)R² wherein R^(y) and R^(z) areindependently selected from the group consisting of hydrogen, alkyl,haloalkyl, aryl, or heteroaryl; each of which may be optionallysubstituted.

“Amidino” refers to —C(NH)(NH₂).

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude phenyl, naphthylenyl, fluorenyl, and anthracenyl. Aryl, however,does not encompass or overlap in any way with heteroaryl defined below.If one or more aryl groups are fused with a heteroaryl, the resultingring system is heteroaryl. If one or more aryl groups are fused with aheterocyclyl, the resulting ring system is heterocyclyl.

“Azido” refers to —N₃.

“Carbamoyl” refers to both an “O-carbamoyl” group which refers to thegroup —O—C(O)NRyR^(z) and an “N-carbamoyl” group which refers to thegroup —NR^(y)C(O)OR^(z), wherein R^(y) and R^(z) are independentlyselected from the group consisting of hydrogen, alkyl, aryl, haloalkyl,or heteroaryl; each of which may be optionally substituted.

“Carboxyl” refers to —C(O)OH.

“Carboxyl ester” refers to both —OC(O)R and —C(O)OR, wherein R ishydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e. the cyclic group having at least one double bond). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Guanidino” refers to —NHC(NH)(NH₂).

“Hydrazino” refers to —NHNH₂.

“Imino” refers to a group —C(NR)R, wherein each R is alkyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

“Heteroalkyl” refers to an alkyl group in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group. The term“heteroalkyl” includes unbranched or branched saturated chain havingcarbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may beindependently replaced with the same or different heteroatomic group.Heteroatomic groups include, but are not limited to, —NR—, —O—, —S—,—S(O)—, —S(O)₂—, and the like, where R is H, alkyl, aryl, cycloalkyl,heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionallysubstituted. Examples of heteroalkyl groups include —OCH₃, —CH₂OCH₃,—SCH₃, —CH₂SCH₃, —NRCH₃, and —CH₂NRCH₃, where R is hydrogen, alkyl,aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may beoptionally substituted. As used herein, heteroalkyl include 1 to 10carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C₁₋₂₀heteroaryl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heteroaryl), or 3 to8 carbon ring atoms (i.e., C₃₋₈ heteroaryl); and 1 to 5 heteroatoms, 1to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1ring heteroatom independently selected from nitrogen, oxygen, andsulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl,pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of thefused-heteroaryl rings include, but are not limited to,benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl,indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, andimidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via eitherring of the fused system. Any aromatic ring, having a single ring ormultiple fused rings, containing at least one heteroatom, is considereda heteroaryl regardless of the attachment to the remainder of themolecule (i.e., through any one of the fused rings). Heteroaryl does notencompass or overlap with aryl as defined above.

“Heterocyclyl” refers to a saturated or unsaturated cyclic alkyl group,with one or more ring heteroatoms independently selected from nitrogen,oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenylgroups (i.e. the heterocyclyl group having at least one double bond),bridged-heterocyclyl groups, fused-heterocyclyl groups, andspiro-heterocyclyl groups. A heterocyclyl may be a single ring ormultiple rings wherein the multiple rings may be fused, bridged, orspiro. Any non-aromatic ring containing at least one heteroatom isconsidered a heterocyclyl, regardless of the attachment (i.e., can bebound through a carbon atom or a heteroatom). Further, the termheterocyclyl is intended to encompass any non-aromatic ring containingat least one heteroatom, which ring may be fused to an aryl orheteroaryl ring, regardless of the attachment to the remainder of themolecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms(i.e., C₂₋₂₀ heterocyclyl), 2 to 12 ring carbon atoms (i.e., C₂₋₁₂heterocyclyl), 2 to 10 ring carbon atoms (i.e., C₂₋₁₀ heterocyclyl), 2to 8 ring carbon atoms (i.e., C₂₋₈ heterocyclyl), 3 to 12 ring carbonatoms (i.e., C₃₋₁₂ heterocyclyl), 3 to 8 ring carbon atoms (i.e., C₂₋₈heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆ heterocyclyl);having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ringheteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independentlyselected from nitrogen, sulfur or oxygen. A heterocyclyl may contain oneor more oxo and/or thioxo groups. Examples of heterocyclyl groupsinclude pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl,azetidinyl, and morpholinyl. As used herein, the term“bridged-heterocyclyl” refers to a four- to ten-membered cyclic moietyconnected at two non-adjacent atoms of the heterocyclyl with one or more(e.g. 1 or 2) four- to ten-membered cyclic moiety having at least oneheteroatom where each heteroatom is independently selected fromnitrogen, oxygen, and sulfur. As used herein, bridged-heterocyclylincludes bicyclic and tricyclic ring systems. Also used herein, the term“spiro-heterocyclyl” refers to a ring system in which a three- toten-membered heterocyclyl has one or more additional ring, wherein theone or more additional ring is three- to ten-membered cycloalkyl orthree- to ten-membered heterocyclyl, where a single atom of the one ormore additional ring is also an atom of the three- to ten-memberedheterocyclyl. Examples of the spiro-heterocyclyl rings include bicyclicand tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl,2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl.Examples of the fused-heterocyclyl rings include, but are not limitedto, 1,2,3,4-tetrahydroisoquinolinyl,1-oxo-1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl,4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl,where the heterocyclyl can be bound via either ring of the fused system.

“Hydroxy” or “hydroxyl” refers to the group —OH. “Hydroxyalkyl” refersto an unbranched or branched alkyl group as defined above, wherein oneor more hydrogen atoms are replaced by a hydroxyl.

“Oxo” refers to the group (═O) or (O).

“Nitro” refers to the group —NO₂.

“Sulfonyl” refers to the group —S(O)₂R, where R is alkyl, haloalkyl,heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl aremethylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

“Alkylsulfonyl” refers to the group —S(O)₂R, where R is alkyl.

“Alkylsulfinyl” refers to the group —S(O)R, where R is alkyl.

“Thiocyanate”-SCN.

“Thiol” refers to the group —SR, where R is alkyl, haloalkyl,heterocyclyl, cycloalkyl, heteroaryl, or aryl.

“Thioxo” or “thione” refer to the group (═S) or (S).

Certain commonly used alternative chemical names may be used. Forexample, a divalent group such as a divalent “alkyl” group, a divalent“aryl” group, etc., may also be referred to as an “alkylene” group or an“alkylenyl” group, an “arylene” group or an “arylenyl” group,respectively. Also, unless indicated explicitly otherwise, wherecombinations of groups are referred to herein as one moiety, e.g.arylalkyl, the last-mentioned group contains the atom by which themoiety is attached to the rest of the molecule.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen.

Some of the compounds exist as tautomers. Tautomers are in equilibriumwith one another. For example, amide containing compounds may exist inequilibrium with imidic acid tautomers. Regardless of which tautomer isshown, and regardless of the nature of the equilibrium among tautomers,the compounds are understood by one of ordinary skill in the art tocomprise both amide and imidic acid tautomers. Thus, the amidecontaining compounds are understood to include their imidic acidtautomers. Likewise, the imidic acid containing compounds are understoodto include their amide tautomers.

Any formula or structure given herein is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, and ¹²⁵I. Various isotopically labeledcompounds of the present disclosure, for example those into whichradioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated. Suchisotopically labelled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also includes “deuterated analogues” of compounds ofFormula I in which from 1 to n hydrogens attached to a carbon atomis/are replaced by deuterium, in which n is the number of hydrogens inthe molecule. Such compounds exhibit increased resistance to metabolismand are thus useful for increasing the half-life of any compound ofFormula I when administered to a mammal, such as a human. See, forexample, Foster, “Deuterium Isotope Effects in Studies of DrugMetabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compoundsare synthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to absorption, distribution, metabolism andexcretion (ADME). Substitution with heavier isotopes such as deuteriummay afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life, reduceddosage requirements and/or an improvement in therapeutic index. An ¹⁸Flabeled compound may be useful for PET or SPECT studies. Isotopicallylabeled compounds of this disclosure and prodrugs thereof can generallybe prepared by carrying out the procedures disclosed in the schemes orin the examples and preparations described below by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent. It is understood that deuterium in this context isregarded as a substituent in the compound of Formula I.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a certain isotope ismeant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In some cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, polymorphs, and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.“Pharmaceutically acceptable salts” or “physiologically acceptablesalts” include, for example, salts with inorganic acids and salts withan organic acid. In addition, if the compounds described herein areobtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid salt. Conversely, if the product is afree base, an addition salt, such as a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare nontoxic pharmaceuticallyacceptable addition salts. Pharmaceutically acceptable acid additionsalts may be prepared from inorganic and organic acids. Salts derivedfrom inorganic acids include hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derivedfrom organic acids include acetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluene-sulfonic acid, salicylic acid, and the like. Likewise,pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines (i.e., NH₂(alkyl)), dialkyl amines (i.e., HN(alkyl)₂),trialkyl amines (i.e., N(alkyl)₃), substituted alkyl amines (i.e.,NH₂(substituted alkyl)), di(substituted alkyl) amines (i.e.,HN(substituted alkyl)₂), tri(substituted alkyl) amines (i.e.,N(substituted alkyl)₃), alkenyl amines (i.e., NH₂(alkenyl)), dialkenylamines (i.e., HN(alkenyl)₂), trialkenyl amines (i.e., N(alkenyl)₃),substituted alkenyl amines (i.e., NH₂(substituted alkenyl)),di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)₂),tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)₃, mono-,di- or tri-cycloalkyl amines (i.e., NH₂(cycloalkyl), HN(cycloalkyl)₂,N(cycloalkyl)₃), mono-, di- or tri-arylamines (i.e., NH₂(aryl),HN(aryl)₂, N(aryl)₃), or mixed amines, etc. Specific examples ofsuitable amines include, by way of example only, isopropylamine,trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidine, halo,haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy,hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid,alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.Polymers or similar indefinite structures arrived at by definingsubstituents with further substituents appended ad infinitum (e.g., asubstituted aryl having a substituted alkyl which is itself substitutedwith a substituted aryl group, which is further substituted by asubstituted heteroalkyl group, etc.) are not intended for inclusionherein. Unless otherwise noted, the maximum number of serialsubstitutions in compounds described herein is three. For example,serial substitutions of substituted aryl groups with two othersubstituted aryl groups are limited to ((substituted aryl)substitutedaryl) substituted aryl. Similarly, the above definitions are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluorines or heteroaryl groups having two adjacentoxygen ring atoms). Such impermissible substitution patterns are wellknown to the skilled artisan. When used to modify a chemical group, theterm “substituted” may describe other chemical groups defined herein.Unless specified otherwise, where a group is described as optionallysubstituted, any substituents of the group are themselves unsubstituted.For example, in some embodiments, the term “substituted alkyl” refers toan alkyl group having one or more substituents including hydroxyl, halo,alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In otherembodiments, the one or more substituents may be further substitutedwith halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is substituted. In other embodiments,the substituents may be further substituted with halo, alkyl, haloalkyl,alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each ofwhich is unsubstituted.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe ait. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds described herein are also provided.Hydrates of the compounds described herein are also provided.

Compounds

Provided herein are compounds that function as modulators of Cot. In oneaspect, provided is a compound having structure of Formula I:

whereinR¹ is hydrogen, —O—R⁷, —N(R⁸)(R⁹), —C(O)—R⁷, —S(O)₂—R⁷, —C₁₋₉ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, orheteroaryl;

-   -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally        substituted with one to four Z¹;        R² is hydrogen, —C(O)—R⁷, —C(O)O—R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z²;        or R¹ and R² together with the nitrogen to which they are        attached to form a heterocyclyl or heteroaryl, wherein each        heterocyclyl or heteroaryl is optionally substituted with one to        four Z²;        R³ is heterocyclyl or heteroaryl, wherein each heterocyclyl or        heteroaryl is optionally substituted with one to four Z³;        R⁴ is aryl, heterocyclyl or heteroaryl, wherein each aryl,        heterocyclyl, or heteroaryl is optionally substituted with one        to four Z⁴;        R⁵ is hydrogen, halo, —CN, —NO₂, —O—R⁷, —N(R⁸)(R⁹), —S(O)—R⁷,        —S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷,        —OC(O)O—R⁷, —OC(O)N(R¹⁰)(R¹¹), —C(O)N(R⁷)₂, —N(R⁷)(C(O)(R⁷),        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉        alkylthio, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl,        and heteroaryl may be optionally substituted with one to four        Z⁵;        R⁶ is —C(O)O—R¹⁶—OP(O)(OR¹²)₂—C(O)—R¹⁶—OP(O)(OR¹²)₂,        —R¹⁶—OP(O)(OR¹²)₂, —C(O)O—R¹⁶—OR¹⁷; —C(O)O—R¹⁶—OH;        —C(O)O—R¹⁶—OC(O)R¹⁷; —C(O)—C(O)OR¹², or —C(O)O—R¹⁶—OC(O)R¹⁷NH₂;        each R⁷ is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,        heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z⁷;        R⁸ and R⁹ at each occurrence are independently hydrogen,        —S(O)₂R¹⁰, —C(O)—R¹⁰, —C(O)O—R¹⁰, —C(O)N(R¹⁰)(R¹¹), C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl        may be optionally substituted with one to four Z⁸;        R¹⁰ and R¹¹ at each occurrence are independently hydrogen, C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅        cycloalkyl, aryl, heterocyclyl, or heteroaryl,    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        optionally is substituted with one to four Z^(1b);        each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, and Z is independently        hydrogen, oxo, halo, —NO₂, —N₃, —CN, thioxo, C₁₋₉ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl,        heteroaryl, heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹²,        —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂R¹⁴)⁺, —N(R¹²)C(O)—R¹²,        —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹³)(R¹⁴), —N(R¹²)S(O)₂(R¹²),        —NR²S(O)₂N(R¹³)(R¹⁴), —NR¹²S(O)₂O(R¹²), —OC(O)R¹²,        —OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂, —OP(O)(OR¹²)₂,        —CH₂P(O)(OR¹²)₂, —OCH₂P(O)(OR¹²)₂, —C(O)OCH₂P(O)(OR¹²)₂,        —P(O)(R²)(OR¹²), —OP(O)(R¹²)(OR¹²), —CH₂P(O)(R¹²)(OR¹²),        —OCH₂P(O)(R¹²)(OR¹²), —C(O)OCH₂P(O)(R¹²)(OR¹²), —P(O)(N(R¹²)₂,        —OP(O)(N(R²)₂, —CH₂P(O)(N(R²)₂, —OCH₂P(O)(N(R¹²)₂),        —C(O)OCH₂P(O)(N(R²)₂, —P(O)(N(R²)₂)(OR²), —OP(O)(N(R²)₂)(OR¹²),        —CH₂P(O)(N(R¹²)₂)(OR¹²). —OCH₂P(O)(N(R¹²)₂)(OR¹²),        —C(O)OCH₂P(O)(N(R²)₂)(OR²), —P(O)(R¹²)(N(R¹²)₂),        —OP(O)(R¹²)(N(R¹²)₂), —CH₂P(O)(R²)(N(R¹²)₂),        —OCH₂P(O)(R²)(N(R²)₂), —C(O)OCH₂P(O)(R¹²)(N(R¹²)₂), —Si(R¹²)₃,        —S—R², —S(O)R², —S(O)(NH)R², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl,        aryl, heteroaryl or heterocyclyl is optionally substituted with        one to four Z^(1a) groups;        each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈        haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹²,        —C(O)O—R², —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,        —N(R¹²)—C(O)R², —N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹³)(R¹⁴),        —N(R¹²)S(O)₂(R¹²), —N(R¹²)S(O)₂—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂O(R²),        —OC(O)R¹², —OC(O)OR², —OC(O)—N(R¹³)(R¹⁴), —Si(R¹²)₃, —S—R²,        —S(O)R², —S(O)(NH)R², —S(O)₂R¹ or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(ib) groups;        each R¹² is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or        heterocyclyl,    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        R¹³ and R¹⁴ at each occurrence are each independently hydrogen,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl,        heteroaryl or heterocyclyl;    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups, or R¹³ and R¹⁴ together with the nitrogen to        which they are attached form a heterocyclyl, wherein said        heterocyclyl is optionally substituted with one to four Z^(1b)        groups;        each R¹ is independently halo, —CN, —NO₂, —O—R⁷, —N(R⁸)(R⁹),        —S(O)—R⁷, —S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷,        —OC(O)O—R⁷, —OC(O)N(R¹⁰)(R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl;        R¹⁶ is —C₁₋₃ alkyl or cyclopropyl optionally substituted with        one to four C₁₋₃ alkyl or cyclopropyl;        R¹⁷ is C₁₋₉ alkyl, cycloalkyl, or heterocyclyl optionally        substituted with one to three R⁶; and        each Z¹, Z², Z⁴, Z⁵, Z⁷, and Z is independently hydrogen, oxo,        halo, —NO₂, —N₃, —CN, thioxo, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl,        heterocyclyl, —O—R¹², —C(O)—R², —C(O)O—R², —C(O)—N(R¹³)(R¹⁴),        —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹²,        —N(R¹²)C(O)N(R¹³)(R¹⁴), —N(R¹²)S(O)₂(R¹²), —NR²S(O)₂N(R¹³)(R¹⁴),        —NR²S(O)₂O(R²), —OC(O)R², —OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂,        —OP(O)(OR¹²)₂, —CH₂P(O)(OR¹²)₂, —OCH₂P(O)(OR²)₂.        —C(O)OCH₂P(O)(OR¹²)₂, —P(O)(R²)(OR¹²), —OP(O)(R²)(OR¹²),        —CH₂P(O)(R¹²)(OR¹²). —OCH₂P(O)(R²)(OR¹²),        —C(O)OCH₂P(O)(R¹²)(OR²), —P(O)(N(R¹²)₂)₂, —OP(O)(N(R²)₂,        —CH₂P(O)(N(R¹)₂)₂, —OCH₂P(O)(N(R¹²)²)₂. —C(O)OCH₂P(O)(N(R¹)₂)₂.        —P(O)(N(R¹²)₂)(OR¹²), —OP(O)(N(R¹²)₂)(OR²),        —CH₂P(O)(N(R¹²)₂)(OR¹²), —OCH₂P(O)(N(R¹²)₂)(OR¹²),        —C(O)OCH₂P(O)(N(R¹²)₂)(OR²). —P(O)(R²)(N(R¹²)₂),        —OP(O)(R²)(N(R¹²)₂), —CH₂P(O)(R¹²)(N(R¹²)₂),        —OCH₂P(O)(R²)(N(R¹²)₂), —C(O)OCH₂P(O)(R²)(N(R¹²)₂), —Si(R¹²)₃,        —S—R², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl,        aryl, heteroaryl or heterocyclyl is optionally substituted with        one to four Z^(1a) groups;        Z⁹ is hydrogen, halo, —CN, or —O—R¹²;        each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈        haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹²,        —C(O)O—R¹², —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R³)₂(R¹⁴)⁺,        —N(R¹²)—C(O)R¹², —N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹³)(R¹⁴),        —N(R¹²)S(O)₂(R¹²), —N(R¹²)S(O)₂—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂O(R¹²),        —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹³)(R¹⁴), —Si(R¹²)₃, —S—R¹²,        —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        each Z^(1b) is independently oxo, thioxo, hydroxy, halo, —NO₂,        —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl,        —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅        cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl), —O(heteroaryl),        —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl),        —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl),        —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂,        —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅ cycloalkyl)₂,        —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,        —N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₂₋₆ alkenyl), —N(C₁₋₉        alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉        alkyl)(C₁₋₈ haloalkyl), —N(C₁₋₉ alkyl)(aryl), —N(C₁₋₉        alkyl)(heteroaryl), —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉        alkyl), —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅        cycloalkyl), —C(O)(C₁₋₄ haloalkyl), —C(O)(aryl),        —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl),        —C(O)O(C₂₋₆ alkenyl), —C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₅        cycloalkyl), —C(O)O(C₁₋₉ haloalkyl), —C(O)O(aryl),        —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂, —C(O)NH(C₁₋₉        alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),        —C(O)NH(C₃₋₁₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl),        —C(O)NH(aryl), —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl),        —C(O)N(C₁₋₉ alkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆        alkynyl)₂, —C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂,        —C(O)N(aryl)₂, —C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂,        —NHC(O)(C₁₋₉ alkyl), —NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆        alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl), —NHC(O)O(C₂₋₆        alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl),        —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl),        —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl), —NHC(O)NH(C₂₋₆        alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈        haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),        —NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl), —S(C₂₋₆ alkenyl),        —S(C₂₋₆ alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈ haloalkyl),        —S(aryl), —S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl),        —N(C₁₋₉ alkyl)S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆        alkynyl), —S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁₋₈ haloalkyl),        —S(O)(aryl), —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉        alkyl), —S(O)₂(C₂₋₆ alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        or —S(O)₂N(C₁₋₉ alkyl)₂;    -   wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl        is optionally substituted with one to four halo, C₁₋₉ alkyl,        C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉ alkyl), —NH(C₃₋₁₅        cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl), —NH(heteroaryl),        —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅ cycloalkyl)₂,        —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅        cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl),        —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),        —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl);        m is 0, 1, or 2;

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof. Some embodiments provide amethod of using (or administering) the compounds of Formula I, oradditional Formula(s) described throughout, in the treatment of adisease or condition in a mammal, such as a human, that is amenable totreatment by a Cot modulator.

In one aspect, provided is a compound having structure of Formula IA:

whereinR¹ is hydrogen, —O—R⁷, —N(R⁸)(R⁹), —C(O)—R⁷, —S(O)₂—R⁷, —C₁₋₉ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, heterocyclyl, aryl, orheteroaryl;

-   -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally        substituted with one to four Z;        R² is hydrogen, —C(O)—R⁷, —C(O)O—R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z²;        or R¹ and R² together with the nitrogen to which they are        attached to form a heterocyclyl or heteroaryl, wherein each        heterocyclyl or heteroaryl is optionally substituted with one to        four Z²;        R³ is heterocyclyl or heteroaryl, wherein each heterocyclyl or        heteroaryl is optionally substituted with one to four Z³;        R⁴ is aryl, heterocyclyl or heteroaryl, wherein each aryl,        heterocyclyl, or heteroaryl is optionally substituted with one        to four Z⁴; R⁵ is hydrogen, halo, —CN, —NO₂, —O—R⁷, —N(R⁸)(R⁹),        —S(O)—R⁷, —S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷,        —OC(O)O—R⁷, —OC(O)N(R¹⁰)(R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉        alkylthio, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl,        and heteroaryl may be optionally substituted with one to four        Z⁵;        R⁶ is —C(O)O—R⁶—OP(O)(OR²)₂—C(O)—R⁶—OP(O)(OR¹²)₂,        —C(O)O—R⁶—OP(O)(OR¹²)₂, —R¹⁶—OP(O)(OR¹²)₂, —C(O)O—R¹⁶—OR¹⁷;        —C(O)O—R¹⁶—OH; —C(O)O—R¹⁶—OC(O)R¹⁷; or —C(O)O—R¹⁶—OC(O)R¹⁷NH₂;        each R⁷ is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,        heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z⁷;        R⁸ and R⁹ at each occurrence are independently hydrogen,        —S(O)₂R¹⁰, —C(O)—R¹⁰, —C(O)O—R¹⁰, —C(O)N(R⁰)(R¹¹), C₁₋₉ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,        aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl        may be optionally substituted with one to four Z⁸;        R¹⁰ and R¹¹ at each occurrence are independently hydrogen, C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅        cycloalkyl, aryl, heterocyclyl, or heteroaryl,    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        optionally is substituted with one to four Z^(b);        each Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, Z⁷, and Z is independently        hydrogen, oxo, halo, —NO₂, —N₃, —CN, thioxo, C₁₋₉ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl,        heteroaryl, heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹²,        —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺,        —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹³)(R¹⁴),        —N(R²)S(O)₂(R¹²), —NR²S(O)₂N(R¹³)(R¹⁴), —NR¹²S(O)₂O(R¹²),        —OC(O)R¹², —OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂, —OP(O)(OR¹²)₂,        —CH₂P(O)(OR¹²)₂, —OCH₂P(O)(OR¹²)₂, —C(O)OCH₂P(O)(OR¹²)₂,        —P(O)(R²)(OR¹²), —OP(O)(R¹²)(OR¹²), —CH₂P(O)(R¹²)(OR¹²),        —OCH₂P(O)(R¹²)(OR²). —C(O)OCH₂P(O)(R¹²)(OR¹²), —P(O)(N(R¹²)₂)₂,        —OP(O)(N(R²)₂, —CH₂P(O)(N(R²)₂, —OCH₂P(O)(N(R¹²)₂).        —C(O)OCH₂P(O)(N(R²)₂. —P(O)(N(R²)₂)(OR²), —OP(O)(N(R²)₂)(OR¹²),        —CH₂P(O)(N(R¹²)₂)(OR¹²). —OCH₂P(O)(N(R¹²)₂)(OR¹²),        —C(O)OCH₂P(O)(N(R²)₂)(OR²), —P(O)(R²)(N(R¹²)₂),        —OP(O)(R¹²)(N(R¹²)₂), —CH₂P(O)(R²)(N(R¹²)₂),        —OCH₂P(O)(R²)(N(R²)₂). —C(O)OCH₂P(O)(R¹²)(N(R¹²)₂), —Si(R¹²)₃,        —S—R², —S(O)R², —S(O)(NH)R², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl,        aryl, heteroaryl or heterocyclyl is optionally substituted with        one to four Z^(1a) groups;        each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈        haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹²,        —C(O)O—R¹², —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R³)₂(R¹⁴)⁺,        —N(R¹²)—C(O)R¹², —N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹³)(R¹⁴),        —N(R¹²)S(O)₂(R¹²), —N(R¹²)S(O)₂—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂O(R¹²),        —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹³)(R¹⁴), —Si(R¹²)₃, —S—R¹²,        —S(O)R¹², —S(O)(NH)R², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        each R¹² is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or        heterocyclyl,    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        R¹³ and R¹⁴ at each occurrence are each independently hydrogen,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl,        heteroaryl or heterocyclyl;    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups, or R¹³ and R¹⁴ together with the nitrogen to        which they are attached form a heterocyclyl, wherein said        heterocyclyl is optionally substituted with one to four Z^(1b)        groups;        each R¹ is independently halo, —CN, —NO₂, —O—R⁷, —N(R₈)(R⁹),        —S(O)—R⁷, —S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷,        —OC(O)O—R⁷, —OC(O)N(R¹⁰)(R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl;        R¹⁶ is —C₁₋₂ alkyl optionally substituted with one to four C₁-2        or cyclopropyl;        R¹⁷ is C₁₋₉alkyl, cycloalkyl, or heterocyclyl optionally        substituted with one to three R¹⁶; and        each Z¹, Z², Z⁴, Z⁵, Z⁷, and Z⁸ is independently hydrogen, oxo,        halo, —NO₂, —N₃, —CN, thioxo, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl,        heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹³)(R¹⁴),        —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹²,        —N(R¹²)C(O)N(R¹³)(R¹⁴), —N(R¹²)S(O)₂(R¹²),        —NR¹²S(O)₂N(R¹³)(R¹⁴), —NR¹²S(O)₂O(R¹²), —OC(O)R¹²,        —OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂, —OP(O)(OR¹²)₂,        —CH₂P(O)(OR¹²)₂. —OCH₂P(O)(OR¹²)₂, —C(O)OCH₂P(O)(OR¹²)₂,        —P(O)(R¹²)(OR¹²), —OP(O)(R¹²)(OR¹²), —CH₂P(O)(R¹²)(OR¹²),        —OCH₂P(O)(R¹²)(OR¹²), —C(O)OCH₂P(O)(R¹²)(OR¹²), —P(O)(N(R¹²)₂),        —OP(O)(N(R¹²)₂), —CH₂P(O)(N(R¹²)₂), —OCH₂P(O)(N(R¹²)₂),        —C(O)OCH₂P(O)(N(R¹²)₂), —P(O)(N(R¹²)₂)(OR¹²),        —OP(O)(N(R¹²)₂)(OR¹²), —CH₂P(O)(N(R¹²)₂)(OR²).        —OCH₂P(O)(N(R¹²)₂)(OR¹²), —C(O)OCH₂P(O)(N(R¹²)₂)(OR¹²),        —P(O)(R¹²)(N(R¹²)₂), —OP(O)(R¹²)(N(R¹²)₂),        —CH₂P(O)(R¹²)(N(R¹²)₂), —OCH₂P(O)(R¹²)(N(R¹²)₂),        —C(O)OCH₂P(O)(R¹²)(N(R¹²)₂), —Si(R¹²)₃, —S—R¹², —S(O)R¹²,        —S(O)(NH)R¹², —S(O)₂R² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl,        aryl, heteroaryl or heterocyclyl is optionally substituted with        one to four Z^(1a) groups;        Z⁹ is hydrogen, halo, —CN, or —O—R¹²;        each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃,        C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈        haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹²,        —C(O)O—R¹², —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R³)₂(R¹⁴)⁺,        —N(R¹²)—C(O)R¹², —N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹³)(R¹⁴),        —N(R¹²)S(O)₂(R¹²), —N(R²)S(O)₂—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂O(R¹²),        —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹³)(R¹⁴), —Si(R¹²)₃, —S—R¹²,        —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;        each Z^(1b) is independently oxo, thioxo, hydroxy, halo, —NO₂,        —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl,        —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅        cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl), —O(heteroaryl),        —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl),        —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁ haloalkyl),        —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂,        —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅ cycloalkyl)₂,        —N(C₁ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,        —N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₂₋₆ alkenyl), —N(C₁₋₉        alky)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉        alkyl)(C₁₋₈ haloalkyl), —N(C₁₋₉ alkyl)(aryl), —N(C₁₋₉        alkyl)(heteroaryl), —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉        alkyl), —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₅        cycloalkyl), —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl),        —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl),        —C(O)O(C₂₋₆ alkenyl), —C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₅        cycloalkyl), —C(O)O(C₁₋₈ haloalkyl), —C(O)O(aryl),        —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂, —C(O)NH(C₁₋₉        alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),        —C(O)NH(C₃₋₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl),        —C(O)NH(aryl), —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl),        —C(O)N(C₁₋₉ alkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆        alkynyl)₂, —C(O)N(C₃₋₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂,        —C(O)N(aryl)₂, —C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂,        —NHC(O)(C₁₋₉ alkyl), —NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₄        alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl), —NHC(O)O(C₂₋₆        alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl),        —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl),        —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl), —NHC(O)NH(C₂₋₆        alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈        haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),        —NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl), —S(C₂₋₆ alkenyl),        —S(C₂₋₆ alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈ haloalkyl),        —S(aryl), —S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl),        —N(C₁₋₉ alkyl)S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆        alkynyl), —S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁₋₈ haloalkyl),        —S(O)(aryl), —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉        alkyl), —S(O)₂(C₂₋₆ alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        or —S(O)₂N(C₁₋₉ alkyl)₂;        wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl        is optionally substituted with one to four halo, C₁₋₉ alkyl,        C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉ alkyl), —NH(C₃₋₁₅        cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl), —NH(heteroaryl),        —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃ is cycloalkyl)₂,        —NHC(O)(C₃₋₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),        —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl),        —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅        cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl),        —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉        alkyl), —S(O)(NH)(C₁₋₉ alkyl), S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅        cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),        —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl),        —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),        —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl);        m is 0, 1, or 2;

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof.

In certain embodiments, the compound of Formula I is represented byFormula IB:

wherein R¹-R⁶, R¹⁵ and m are as described herein.

In certain embodiments, the compound of Formula I is represented byFormula IC:

wherein R¹-R⁶, R¹⁵ and m are as described herein.

In certain embodiments, m is 0. In certain embodiments, R² is hydrogen.

In certain embodiments, the compound of Formula I is represented byFormula II:

-   wherein R is hydrogen, —O—R⁷, —N(R⁸)(R⁹), —C(O)—R⁷, —S(O)₂—R⁷, —C₁₋₉    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, heterocyclyl,    aryl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅        cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally        substituted with one to four Z;-   R² is hydrogen, —C(O)—R⁷, —C(O)O—R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,    heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z²;-   or R¹ and R² together with the nitrogen to which they are attached    form a heterocyclyl or heteroaryl, wherein each heterocyclyl or    heteroaryl is optionally substituted with one to four Z²;-   R³ is hydrogen, oxo, halo, —NO₂, —N₃, —CN, thioxo, C₁₋₉ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl,    heteroaryl, heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹²,    —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, —N(R¹²)C(O)—R¹²,    —N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹³)(R¹⁴), —N(R¹²)S(O)₂(R¹²),    —NR¹²S(O)₂N(R¹³)(R¹⁴), —NR¹²S(O)₂₀(R¹²), —OC(O)R¹²,    —OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂, —OP(O)(OR¹²)₂, —CH₂P(O)(OR¹²)₂,    —OCH₂P(O)(OR¹²)₂, —C(O)OCH₂P(O)(OR¹²)₂, —P(O)(R¹²)(OR¹²),    —OP(O)(R¹²)(OR¹²), —CH₂P(O)(R¹²)(OR¹²), —OCH₂P(O)(R¹²)(OR¹²),    —C(O)OCH₂P(O)(R¹²)(OR¹²). —P(O)(N(R¹²)₂), —OP(O)(N(R¹²)₂),    —CH₂P(O)(N(R¹²)₂), —OCH₂P(O)(N(R¹²)₂), —C(O)OCH₂P(O)(N(R²²)₂,    —P(O)(N(R¹²)₂)(OR¹²), —OP(O)(N(R¹²)₂)(OR¹²),    —CH₂P(O)(N(R¹²)₂)(OR¹²), —OCH₂P(O)(N(R¹²)₂)(OR¹²),    —C(O)OCH₂P(O)(N(R¹²)₂)(OR¹²), —P(O)(R²)(N(R¹²)₂),    —OP(O)(R¹²)(N(R¹²)₂), —CH₂P(O)(R¹²)(N(R¹²)₂),    —OCH₂P(O)(R¹²)(N(R¹²)₂), —C(O)OCH₂P(O)(R¹²)(N(R¹²)₂), —Si(R¹²)₃,    —S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl,        aryl, heteroaryl or heterocyclyl is optionally substituted with        one to four Z^(1a) groups;-   R⁴ is aryl, heterocyclyl or heteroaryl, wherein each aryl,    heterocyclyl, or heteroaryl is optionally substituted with one to    four Z⁴;-   R⁵ is hydrogen, halo, —CN, —NO₂, —O—R⁷, —N(R⁸)(R⁹), —S(O)—R⁷,    —S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —OC(O)—R⁷, —C(O)O—R⁷, —OC(O)O—R⁷,    —OC(O)N(R¹⁰)(R¹¹), —C(O)N(R⁷)₂, —N(R⁷)C(O)(R⁷), C₁₋₉ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁₋₉ alkylthio, C₁₋₆ haloalkyl, C₃₋₁₅    cycloalkyl, aryl, heterocyclyl, or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₉        alkylthio, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl,        and heteroaryl may be optionally substituted with one to four        Z⁵;-   R⁶ is —C(O)O—R⁶—OP(O)(OR¹²)₂;-   each R⁷ is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or    heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z⁷;-   R⁸ and R⁹ at each occurrence are independently hydrogen, —S(O)₂R¹⁰,    —C(O)—R¹⁰, —C(O)O—R¹⁰, —C(O)N(R¹⁰)(R¹¹), C₁₋₉ alkyl, C₂₋₆ alkenyl,    C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl,    or heteroaryl;    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl        may be optionally substituted with one to four Z⁸;-   R¹⁰ and R¹¹ at each occurrence are independently hydrogen, C₁₋₉    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl,    aryl, heterocyclyl, or heteroaryl,    -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        optionally is substituted with one to four Z^(1b);-   each R¹² is independently hydrogen, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or heterocyclyl,    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;-   R¹³ and R¹⁴ at each occurrence are each independently hydrogen, C₁₋₉    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl,    heteroaryl or heterocyclyl;    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups, or R¹³ and R¹⁴ together with the nitrogen to        which they are attached form a heterocyclyl, wherein said        heterocyclyl is optionally substituted with one to four Z^(1b)        groups;-   R¹⁶ is —C₁₋₂ alkyl optionally substituted with one to four C₁-2 or    cyclopropyl;-   and-   each Z¹, Z², Z⁴, Z⁵, Z⁷, and Z⁸ is independently hydrogen, oxo,    halo, —NO₂, —N₃, —CN, thioxo, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl,    heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹³)(R¹⁴),    —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹²,    —N(R¹²)C(O)N(R¹³)(R¹⁴), —N(R¹²)S(O)₂(R¹²), —NR²S(O)₂N(R¹³)(R¹⁴),    —NR²S(O)₂O(R¹²), —OC(O)R², —OC(O)—N(R¹³)(R¹⁴), —P(O)(OR¹²)₂,    —OP(O)(OR¹²)₂, —CH₂P(O)(OR¹²)₂. —OCH₂P(O)(OR¹²)₂,    —C(O)OCH₂P(O)(OR¹²)₂, —P(O)(R²)(OR¹²), —OP(O)(R²)(OR¹²),    —CH₂P(O)(R¹²)(OR¹²), —OCH₂P(O)(R¹²)(OR¹²), —C(O)OCH₂P(O)(R²)(OR¹²),    —P(O)(N(R¹²)₂)₂, —OP(O)(N(R²)₂, —CH₂P(O)(N(R²)₂, —OCH₂P(O)(N(R²)₂,    —C(O)OCH₂P(O)(N(R²)₂, —P(O)(N(R¹²)₂)(OR¹²), —OP(O)(N(R¹²)₂)(OR²),    —CH₂P(O)(N(R¹²)₂)(OR¹²). —OCH₂P(O)(N(R¹²)₂)(OR²).    —C(O)OCH₂P(O)(N(R¹²)₂)(OR¹²), —P(O)(R²)(N(R²)₂),    —OP(O)(R²)(N(R¹²)₂), —CH₂P(O)(R¹²)(N(R¹²)₂),    —OCH₂P(O)(R¹²)(N(R¹²)₂), —C(O)OCH₂P(O)(R¹²)(N(R¹²)₂), —Si(R¹²)₃,    —S—R², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl,        aryl, heteroaryl or heterocyclyl is optionally substituted with        one to four Z^(1a) groups;-   Z⁹ is hydrogen, halo, —CN, or —O—R¹²;-   each Z^(1a) is independently oxo, halo, thioxo, —NO₂, —CN, —N₃, C₁₋₉    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl,    aryl, heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹², —C(O)O—R²,    —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R³)₂(R¹⁴)⁺, —N(R¹²)—C(O)R²,    —N(R¹²)C(O)O(R¹²), —N(R²)C(O)N(R¹³)(R¹⁴), —N(R²)S(O)₂(R¹²),    —N(R¹²)S(O)₂—N(R¹³)(R¹⁴), —N(R¹²)S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹²,    —OC(O)—N(R¹³)(R¹⁴), —Si(R¹²)₃, —S—R¹², —S(O)R¹², —S(O)(NH)R¹²,    —S(O)₂R¹² or —S(O)₂N(R¹³)(R¹⁴);    -   wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl is optionally substituted with one to        four Z^(1b) groups;-   each Z^(1b) is independently oxo, thioxo, hydroxy, halo, —NO₂, —N₃,    —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈    haloalkyl, aryl, heteroaryl, heterocyclyl, —O(C₁₋₉ alkyl), —O(C₂₋₆    alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅ cycloalkyl), —O(C₁₄ haloalkyl),    —O(aryl), —O(heteroaryl), —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl),    —NH(C₂₋₆ alkenyl), —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁    haloalkyl), —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉    alkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅    cycloalkyl)₂, —N(C₁ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,    —N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₂₋₆ alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆    alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₁    haloalkyl), —N(C₁₋₉ alkyl)(aryl), —N(C₁₋₉ alkyl)(heteroaryl),    —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉ alkyl), —C(O)(C₂₋₆    alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅ cycloalkyl), —C(O)(C₁₋₈    haloalkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl),    —C(O)O(C₁₋₉ alkyl), —C(O)O(C₂₋₆ alkenyl), —C(O)O(C₂₋₆ alkynyl),    —C(O)(C₃₋₁₅ cycloalkyl), —C(O)O(C₁₋₈ haloalkyl), —C(O)O(aryl),    —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂, —C(O)NH(C₁₋₉    alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₄ alkynyl), —C(O)NH(C₃₋₁₅    cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl), —C(O)NH(aryl),    —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,    —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆ alkynyl)₂, —C(O)N(C₃₋₁₅    cycloalkyl)₂, —C(O)N(C₁-haloalkyl)₂, —C(O)N(aryl)₂,    —C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂, —NHC(O)(C₁₋₉ alkyl),    —NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆ alkynyl), —NHC(O)(C₃₋₁₅    cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl),    —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl),    —NHC(O)O(C₂₋₆ alkenyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅    cycloalkyl), —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl),    —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl),    —NHC(O)NH(C₂₋₆ alkenyl), —NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅    cycloalkyl), —NHC(O)NH(C₁₋₈ haloalkyl), —NHC(O)NH(aryl),    —NHC(O)NH(heteroaryl), —NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl),    —S(C₂₋₆ alkenyl), —S(C₂₋₆ alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈    haloalkyl), —S(aryl), —S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉    alkyl), —N(C₁₋₉ alkyl)S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂,    —S(O)(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl),    —S(O)(C₂₋₆ alkynyl), —S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁₋₈ haloalkyl),    —S(O)(aryl), —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉    alkyl), —S(O)₂(C₂₋₆ alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅    cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl), —S(O)₂(aryl),    —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl), or    —S(O)₂N(C₁₋₉ alkyl)₂;    -   wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl        is optionally substituted with one to four halo, C₁₋₉ alkyl,        C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉ alkyl), —NH(C₃₋₁₅        cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl), —NH(heteroaryl),        —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅ cycloalkyl)₂,        —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁ haloalkyl), —NHC(O)(aryl),        —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉        alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),        —NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),        —NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉        alkyl), S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈        haloalkyl), —S(O)₂(aryl), —S(O)₂(heteroaryl),        —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉ alkyl), —S(O)₂N(C₁₋₉        alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl),        —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl);        or a pharmaceutically acceptable salt, stereoisomer, mixture of        stereoisomers, or deuterated analog thereof.

In certain embodiments, R^(3a) is hydrogen, C₁₋₉ alkyl, C₃₋₁₅cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C₁₋₉ alkyl,C₃₋₁₅ cycloalkyl, aryl, or heterocyclyl, may be optionally substitutedwith one to four substituents independently selected from the groupconsisting of cyano, halo, —O—R¹², —C(O)—R¹², —OC(O)—R¹², —C(O)O—R¹²,—C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), —N(R¹³)₂(R¹⁴)⁺, —S(O)₂—R¹², —Si(R¹²)₃,C₁₋₉ alkyl, C₁₋₈ haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, andheteroaryl; and wherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, heterocyclyl,or aryl may be optionally substituted with one to three substituentsindependently selected from the group consisting of halo, —O(C₁₋₉alkyl), —C(O)N(C₁₋₉ alkyl)₂, C₁₋₉ alkyl, and heterocyclyl.

In some embodiments, R³ is hydrogen or C₁₋₉ alkyl; wherein said C₁₋₉alkyl may be optionally substituted with one to four substituentsindependently selected from the group consisting of cyano, halo, —O—R¹²,—C(O)—R¹², —OC(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴),—N(R¹³)₂(R¹⁴)⁺, —S(O)₂—R¹², —Si(R¹²)₃, C₁₋₈ haloalkyl, C₃₋₁₅ cycloalkyl,aryl, heterocyclyl, and heteroaryl; and wherein said C₃₋₁₅ cycloalkyl,aryl, heterocyclyl, or heteroaryl may be optionally substituted with oneto three substituents independently selected from the group consistingof halo, —O(C₁₋₉ alkyl), —C(O)N(C₁₋₉ alkyl)₂, C₁₋₉ alkyl, andheterocyclyl, or a pharmaceutically acceptable salt thereof.

In certain embodiments, R^(3a) is C₃₋₁₅ cycloalkyl, heterocyclyl, aryl,or heteroaryl; wherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, aryl, orheterocyclyl, may be optionally substituted with one to foursubstituents independently selected from the group consisting of cyano,halo, —O—R¹², —C(O)—R¹², —OC(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹³)(R¹⁴),—N(R¹³)(R¹⁴), —N(R³)₂(R¹⁴)⁺, —S(O)₂—R¹², —Si(R¹²)₃, C₁₋₉ alkyl, C₁₋₈haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl; andwherein said C₁₋₉ alkyl, C₃₋₁₅ cycloalkyl, heterocyclyl, or aryl may beoptionally substituted with one to three substituents independentlyselected from the group consisting of halo, —O(C₁₋₉ alkyl), —C(O)N(C₁₋₉alkyl)₂, C₁₋₉ alkyl, and heterocyclyl.

In some embodiments, R³ is C₃₋₁₅ cycloalkyl optionally substituted withone to four substituents independently selected from the groupconsisting of cyano, halo, —O—R¹², —C(O)O—R¹², —OC(O)—R¹², —N(R¹³)(R¹⁴),—N(R³)₂(R¹⁴)⁺, C₁₋₉ alkyl, C₁₋₈ haloalkyl, heterocyclyl, and heteroaryl.

In certain embodiments, R⁴ is aryl optionally substituted with one tothree substituents independently selected from the group consisting of—CN, halo, —O—R², —C(O)—R², —C(O)O—R², —S(O)₂—R¹², —N(R¹²)C(O)—R¹²,—N(R¹²)S(O)₂R¹², —C(O)N(R¹³)(R¹⁴), —N(R¹³)(R¹⁴), C₁₋₉ alkyl, C₃₋₁₅cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said C₁₋₉ alkyl,C₃₋₁₅ cycloalkyl, or heteroaryl may be optionally substituted with oneto three substituents independently selected from the group consistingof halo, —CN, —O—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl, and heterocyclyl.

In some embodiments, R⁴ is

In some embodiments, R⁴ is heterocyclyl, or heteroaryl optionallysubstituted with one to three substituents independently selected fromthe group consisting of cyano, halo and C₁₋₉ alkyl.

In certain embodiments, R⁴ is heterocyclyl or heteroaryl; and saidheterocyclyl or heteroaryl is optionally substituted with one to threesubstituents independently selected from the group consisting of —CN,halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl, C₁₋₈haloalkyl, andheterocyclyl.

In certain embodiments, R⁴ is heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof —CN, halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl,C₁₋₈haloalkyl, and heterocyclyl.

In some embodiments, R⁴ is heterocyclyl optionally substituted with oneto three substituents independently selected from the group consistingof —CN, halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl,C₁₋₈haloalkyl, and heterocyclyl, or a pharmaceutically acceptable saltthereof.

In some embodiments, R⁴ is

and

q is 0, 1, 2, 3 or 4, and

wherein Z⁴ is independently selected from the group consisting of —CN,halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl, C₁₋₈haloalkyl, andheterocyclyl.

In some embodiments, R⁴ is

q is 0, 1, 2, 3 or 4, and

wherein Z⁴ is independently selected from the group consisting of —CN,halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl, C₁₋₈haloalkyl, andheterocyclyl.

In some embodiments, R⁴ is

wherein Z⁴ is independently selected from the group consisting of —CN,halo, —O—R¹², —C(O)—R¹², —N(R¹³)(R¹⁴), C₁₋₉ alkyl, C₁₋₈haloalkyl, andheterocyclyl.

In certain embodiments, R⁴ is

In certain embodiments, R⁵ is hydrogen, halo, —CN, —O—R⁷, —S(O)—R⁷,—S(O)₂R⁷, —S(O)₂N(R⁷)₂, —C(O)R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, or heteroaryl;wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl,aryl, heterocyclyl, and heteroaryl may be optionally substituted withone to four Z⁵.

In certain embodiments, R⁵ is hydrogen, halo, —CN, —C(O)R⁷, orheteroaryl. In one embodiment, R⁵ is —CN, halo or —O—R⁷. In certainembodiments, R⁵ is hydrogen, halo, —CN, —C(O)R⁷, —O—R⁷, —S(O)₂R⁷ orheteroaryl. In one embodiment, R⁵ is halo.

In certain embodiments, R⁵ is 1H-pyrazol-4-yl, 1-hydroxyethyl,1-methyl-1H-pyrazol-4-15 yl, 4-(acetylamino)phenyl,6-fluoropyridin-3-yl, methyl acetyl, bromo, chloro, cyano, cyclopropyl,dimethylaminocarbonyl, ethynyl, fluoro, iodo, methoxy, methyl, hydroxyl,phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, acetyl,methylsulfonyl or trifluoromethyl. In one embodiment, R⁵ is chloro.

In some embodiments, R⁶ is —C(O)O—R¹⁶—OP(O)(OH)₂.

In some embodiments, R⁶ is

In some embodiments, R⁶ is

In some embodiments, R⁶ is

In some embodiments, R⁶ is

In some embodiments, R¹⁶ is C₂₋₃ alkyl. In some embodiments, R¹⁶ ismethyl. In some embodiments, R¹⁶ is ethyl. In some embodiments, R¹⁶ isunsubstituted. In some embodiments, R¹⁶ is substituted by one, two,three, or four methyl groups. In some embodiments, R¹⁶ is substituted byone or two methyl groups. In some embodiments, R¹⁶ is substituted by oneor two cyclopropyl groups.

In some embodiments, Z⁹ is hydrogen.

Some embodiments provide a compound of formula:

In one embodiment, m is 0. In another embodiment, m is 1.

Some embodiments of the disclosure include compounds of the followingFormula III:

whereinR¹, R², R³, R⁴, R⁵, R¹⁵, and m are as described herein, andR¹⁸ is hydrogen, —C(O)—R⁷, —C(O)O—R⁷, —C(O)N(R⁷)₂, C₁₋₉ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₅ cycloalkyl, aryl,heterocyclyl, or heteroaryl;

-   -   wherein each C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₅ cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one to four Z⁶;        or a pharmaceutically acceptable salt, tautomer, stereoisomer,        mixture of stereoisomers, prodrug, or deuterated analog thereof.

In general, the specific compounds exemplified herein are named usingChemBioDraw Ultra. However, it is understood that other names may beused to identify compounds of the same structure. For example, thecompounds may also be named using other nomenclature systems and symbolsthat are commonly recognized in the art of chemistry including, forexample, Chemical Abstract Service (CAS) and International Union of Pureand Applied Chemistry (IUPAC). Other compounds or radicals may be namedwith common names, or systematic or non-systematic names.

In certain embodiments, provided are optical isomers, racemates, orother mixtures thereof of the compounds described herein orpharmaceutically acceptable salts or a mixture thereof. In thosesituations, the single enantiomer or diastereomer, i.e., opticallyactive form, can be obtained by asymmetric synthesis or by resolution.Resolution can be accomplished, for example, by conventional methodssuch as crystallization in the presence of a resolving agent, orchromatography, using for example, a chiral high pressure liquidchromatography (HPLC) column.

Compositions provided herein can include a compound described herein orpharmaceutically acceptable salts, isomer, or a mixture thereof mayinclude racemic mixtures, or mixtures containing an enantiomeric excessof one enantiomer or single diastereomers or diastereomeric mixtures.All such isomeric forms of these compounds are expressly included hereinthe same as if each and every isomeric form were specifically andindividually listed.

A composition comprising a mixture of enantiomers (or diastereomers) ofa compound described herein or a pharmaceutically acceptable saltthereof, is also provided herein. In some embodiments, the compositioncomprises a single enantiomer of the compound and is substantially freeof the other enantiomer. In certain embodiments, the compound of FormulaI (or another Formula as described herein) contains one or moreadditional stereogenic atom(s) (e.g., at R¹ and/or R³). In suchinstances, the composition may contain a mixture of diastereomers. Insome embodiments, the composition comprises a single enantiomer of thecompound and is substantially free (i.e., having less than or about 40%,30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.05%, or 0.01%) of one or morediastereomers.

Accordingly, in certain embodiments, provided is a compositioncomprising a mixture of Formula IA-1, or a pharmaceutically acceptablesalt thereof, and Formula IB-1, or a pharmaceutically acceptable saltthereof.

wherein m, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁵ are as defined herein.

In one embodiment, the mixture is a racemic mixture. In otherembodiments, the composition comprises a mixture of Formula IA-1, or apharmaceutically acceptable salt thereof, and Formula IB-1, or apharmaceutically acceptable salt thereof, wherein Formula IA-1 ispresent in excess of over Formula IB-1, or a pharmaceutically acceptablesalt thereof. In certain embodiments, provided is a compositionsubstantially free of Formula IB-1, having less than or about 40%, 30%,25%, 20%, 15%, 10%, 5%, 1%, 0.05%, or 0.01% of compounds of FormulaIB-1.

In other embodiments, the mixture comprises compounds of Formula IA-1and IB-1 in a a molar ratio of at least or about 3:1, at least or about4:1, at least or about 5:1, at least or about 6:1, at least or about7:1, at least or about 8:1, at least or about 9:1, at least or about10:1, at least or about 11:1, at least or about 12:1, at least or about20:1, at least or about 30:1, at least or about 40:1, at least or about80:1, at least or about 160:1, or at least or about 320:1, respectively.

In certain embodiments, provided are also chelates, non-covalentcomplexes, and mixtures thereof, of the compounds described herein or apharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof. A “chelate” isformed by the coordination of a compound to a metal ion at two (or more)points. A “non-covalent complex” is formed by the interaction of acompound and another molecule wherein a covalent bond is not formedbetween the compound and the molecule. For example, complexation canoccur through van der Waals interactions, hydrogen bonding, andelectrostatic interactions (also called ionic bonding).

Therapeutic Uses of the Compounds

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or a pharmaceutically acceptable salt,tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuteratedanalog thereof means an amount sufficient to effect treatment whenadministered to a subject, to provide a therapeutic benefit such asamelioration of symptoms or slowing of disease progression. For example,a therapeutically effective amount may be an amount sufficient todecrease a symptom of a disease or condition responsive to inhibition ofCot activity. The therapeutically effective amount may vary depending onthe subject, and disease or condition being treated, the weight and ageof the subject, the severity of the disease or condition, and the mannerof administering, which can readily be determined by one or ordinaryskill in the art.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. “Inhibition of activity of Cot” orvariants thereof refers to a decrease in activity in Cot as a direct orindirect response to the presence of a compound of the presentapplication relative to the activity Cot in the absence of the compoundof the present application. “Inhibition of Cot” refers to a decrease inCot activity as a direct or indirect response to the presence of acompound described herein relative to the activity of Cot in the absenceof the compound described herein. In some embodiments, the inhibition ofCot activity may be compared in the same subject prior to treatment, orother subjects not receiving the treatment.

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex v/vo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. Exemplary tissue samples includetumors and biopsies thereof. In this context, the compounds andcompositions described herein may be used for a variety of purposes,including therapeutic and experimental purposes. For example, thecompounds and compositions described herein may be used ex vivo todetermine the optimal schedule and/or dosing of administration of a Cotinhibitor for a given indication, cell type, individual, and otherparameters. Information gleaned from such use may be used forexperimental purposes or in the clinic to set protocols for in vivotreatment. Other ex vivo uses for which the compounds and compositionsdescribed herein may be suited are described below or will becomeapparent to those skilled in the art. The selected compounds may befurther characterized to examine the safety or tolerance dosage in humanor non-human subjects. Such properties may be examined using commonlyknown methods to those skilled in the art.

The compounds disclosed herein are useful for the treatment of diseasesor conditions mediated by Cot. Non-limiting examples of diseases orconditions mediated by Cot include, without limitation, cancer,diabetes, and inflammatory diseases such as rheumatoid arthritis (RA),multiple sclerosis (MS), inflammatory bowel disease (IBD), sepsis,psoriasis, misregulated TNF expression, graft rejection, and liverdisease.

In further embodiments, the methods are provided for alleviating asymptom of a disease or disorder mediated by Cot. In some embodiments,the methods include identifying a mammal having a symptom of a diseaseor disorder mediated by Cot, and providing to the mammal an amount of acompound as described herein effective to ameliorate (i.e., lessen theseverity of) the symptom.

In some embodiments, the disease or condition mediated by Cot is cancer.In some embodiments, the cancer is Burkitt's lymphoma, Hodgkin'slymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma(iNHL), refractory iNHL, multiple myeloma (MM), chronic myeloid leukemia(CML), acute lymphocytic leukemia (ALL), B-cell ALL, acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocyticlymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferativedisease (MPD), mantle cell lymphoma (MCL), follicular lymphoma (FL),Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma,diffuse large B-cell lymphoma (DLBCL), or marginal zone lymphoma (MZL).In one embodiment, the cancer is minimal residual disease (MRD). Inadditional embodiment, the cancer is selected from Hodgkin's lymphoma,non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL),and refractory iNHL. In certain embodiment, the cancer is indolentnon-Hodgkin's lymphoma (iNHL). In some embodiment, the cancer isrefractory iNHL. In one embodiment, the cancer is chronic lymphocyticleukemia (CLL). In other embodiment, the cancer is diffuse large B-celllymphoma (DLBCL).

In certain embodiments, the cancer is a solid tumor is selected from thegroup consisting of pancreatic cancer; bladder cancer, colorectalcancer, breast cancer, including metastatic breast cancer; prostatecancer, including androgen-dependent and androgen-independent prostatecancer; kidney or renal cancer, including, e.g., metastatic renal cellcarcinoma; hepatocellular cancer; lung cancer, including, e.g.,non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC),and adenocarcinoma of the lung; ovarian cancer, including, e.g.,progressive epithelial or primary peritoneal cancer, cervical cancer;gastric cancer, esophageal cancer; head and neck cancer, including,e.g., squamous cell carcinoma of the head and neck; melanoma;neuroendocrine cancer, including metastatic neuroendocrine tumors; braintumors, including, e.g., glioma, anaplastic oligodendroglioma, adultglioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer;and soft tissue sarcoma, hepatic carcinoma, rectal cancer, penilecarcinoma, vulval cancer, thyroid cancer, salivary gland carcinoma,endometrial or uterine carcinoma, hepatoma, hepatocellular cancer, livercancer, gastric or stomach cancer including gastrointestinal cancer,cancer of the peritoneum, squamous carcinoma of the lung,gastroesophagal cancer, biliary tract cancer, gall bladder cancer,colorectal/appendiceal cancer, squamous cell cancer (e.g., epithelialsquamous cell cancer).

Any of the methods of treatment provided can be used to treat cancer atvarious stages. By way of example, the cancer stage includes but is notlimited to early, advanced, locally advanced, remission, refractory,reoccurred after remission and progressive.

In some embodiments, the disease or condition mediated by Cot isdiabetes, which includes any metabolic disorder characterized byimpaired insulin production and glucose tolerance. In some embodiments,diabetes includes type 1 and type 2 diabetes, gestational diabetes,prediabetes, insulin resistance, metabolic syndrome, impaired fastingglycaemia and impaired glucose tolerance. Type 1 diabetes is also knownas Insulin Dependent Diabetes Mellitus (IDDM). Type 2 is also known asNon-Insulin-Dependent Diabetes Mellitus (NIDDM).

In some embodiments, the disease or condition mediated by Cot is aninflammatory disease or LPS induced endotoxin shock. In someembodiments, the disease is an autoimmune disease.

In some embodiments, the inflammatory disease is acid-induced lunginjury, Addison's disease, adrenal hyperplasia, adrenocorticalinsufficiency, adult-onset Still's disease, adult respiratory distresssyndrome (ARDS), age-related macular degeneration, alcoholic hepatitis,alcoholic liver disease, allergen-induced asthma, allergicbronchopulmonary, allergic conjunctivitis, allergic contact dermatitis,allergies, allergic encephalomyelitis, allergic neuritis, allograftrejection, alopecia, alopecia areata, Alzheimer's disease, amyloidosis,amyotrophic lateral sclerosis, angina pectoris, angioedema,angiofibroma, anhidrotic ectodermal dysplasia-ill, anti-glomerularbasement membrane disease, antigen-antibody complex mediated diseases,ankylosing spondylitis, antiphospholipid syndrome, aphthous stomatitis,appendicitis, arthritis, ascites, aspergillosis, asthma,atherosclerosis, atherosclerotic plaques, atopic dermatitis, atrophicthyroiditis, autoimmune diseases, autoimmune hemolytic anemia (immunepancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmunepolyendocrinopathies, autoimmune thrombocytopenia (idiopathicthrombocytopenic purpura, immune-mediated thrombocytopenia), autoimmunehepatitis, autoimmune thyroid disorders, autoinflammatory diseases, backpain, Bacillus anthracis infection, Bechet's disease, bee sting-inducedinflammation, Behget's syndrome, Bell's palsy, berylliosis, Blausyndrome, bone pain, bronchiolitis, bullous pemphigoid (BP) asthma,burns, bursitis, cardiac hypertrophy, carpal tunnel syndrome,Castleman's disease, catabolic disorders, cataracts, Celiac disease,cerebral aneurysm, chemical irritant-induced inflammation,chorioretinitis, chronic atypical neutrophilic dermatosis withlipodystrophy and elevated temperature (CANDLE) syndrome, chronic heartfailure, chronic lung disease of prematurity, chronic obstructivepulmonary disease (COPD), chronic pancreatitis, chronic prostatitis,chronic recurrent multifocal osteomyelitis, cicatricial alopecia,colitis, complex regional pain syndrome, complications of organtransplantation, conjunctivitis, connective tissue disease, contactdermatitis, comeal graft neovascularization, comeal ulcer, Crohn'sdisease, cryopyrin-associated periodic syndromes, cutaneous lupuserythematosus (CLE), cyrptococcosis, cystic fibrosis, deficiency of theinterleukin-1 receptor antagonist (DIRA), dermatitis, dermatitisendotoxemia, dermatomyositis, diabetic macular edema, diverticulitis,eczema, encephalitis, endometriosis, endotoxemia, eosinophilicpneumonias, epicondylitis, epidermolysis bullosa, erythema multiforme,erythroblastopenia, esophagitis, familial amyloidotic polyneuropathy,familial cold urticarial, familial Mediterranean fever, fetal growthretardation, fibromyalgia, fistulizing Crohn's disease, food allergies,giant cell arteritis, glaucoma, glioblastoma, glomerular disease,glomerular nephritis, glomerulonephritis, gluten-sensitive enteropathy,gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatoushepatitis, Graves' disease, growth plate injuries, Guillain-Barresyndrome, gut diseases, hair loss, Hashimoto's thyroiditis, head injury,headache, hearing loss, heart disease, hemangioma, hemolytic anemia,hemophilic joints, Henoch-Scholein purpura, hepatitis, hereditaryperiodic fever syndrome, heritable disorders of connective tissue,herpes zoster and simplex, hidradenitis suppurativa (HS), hipreplacement, Hodgkin's disease, Huntington's disease, hyaline membranedisease, hyperactive inflammatory response, hyperammonemia,hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES),hyperimmunoglobulinemia D with recurrent fever (HIDS), hypersensitivitypneumonitis, hypertropic bone formation, hypoplastic and other anemias,hypoplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy,Idiopathic inflammatory myopathies (dermatomyositis, polymyositis),idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura,immunoglobulin nephropathies, immune complex nephritis, immunethrombocytopenic purpura (ITP), incontinentia pigmenti (IP,Bloch-Siemens syndrome), infectious mononucleosis, infectious diseasesincluding viral diseases such as AIDS (HIV infection), hepatitis A, B,C, D, and E, herpes; inflammation, inflammation of the CNS, inflammatorybowel disease (IBD), inflammatory disease of the lower respiratory tractincluding bronchitis or chronic obstructive pulmonary diseases,inflammatory disease of the upper respiratory tract including the noseand sinuses such as rhinitis or sinusitis, inflammatory diseases of therespiratory tract, inflammatory ischemic event such as stroke or cardiacarrest, inflammatory lung disease, inflammatory myopathy such asmyocarditis, inflammatory liver disease, inflammatory neuropathy,inflammatory pain, insect bite-induced inflammation, interstitialcystitis, interstitial lung disease, iritis, irritant-inducedinflammation, ischemia/reperfusion, joint replacement, juvenilearthritis, juvenile rheumatoid arthritis, keratitis, kidney injurycaused by parasitic infections, kidney transplant rejection,leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS),Lambert-Eaton myasthenic syndrome, Loeffler's syndrome, lupus, lupusnephritis, Lyme disease, Marfan syndrome (MFS), mast cell activationsyndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixedconnective tissue disease, Muckle-Wells syndrome (urticaria deafnessamyloidosis), mucositis, multiple organ injury syndrome, multiplesclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG),myelodysplastic syndrome, myocarditis, myositis, nasal sinusitis,necrotizing enterocolitis, neonatal onset multisystem inflammatorydisease (NOMID), neovascular glaucoma, nephrotic syndrome, neuritis,neuropathological diseases, non-allergen induced asthma, obesity, ocularallergy, optic neuritis, organ transplant rejection, Osier-Webersyndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis,osteoporosis, osterarthritis, otitis, pachyonychia congenita, Paget'sdisease, Paget's disease of bone, pancreatitis, Parkinson's disease,pediatric rheumatology, pelvic inflammatory disease, pemphigus,pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodicfever, periodontitis, peritoneal endometriosis, pernicious anemia(Addison's disease), pertussis, PFAPA (periodic fever aphthouspharyngitis and cervical adenopathy), pharyngitis and adenitis (PFAPAsyndrome), plant irritant-induced inflammation, pneumocystis infection,pneumonia, pneumonitis, poison ivy/urushiol oil-induced inflammation,polyarthritis nodosa, polychondritis, polycystic kidney disease,polymyalgia rheumatic, giant cell arteritis, polymyositis, pouchitis,preperfusion injury and transplant rejection, primary biliary cirrhosis,primary pulmonary hypertension, primary sclerosing cholangitis (PSC),proctitis, psoriasis, psoriasis vulgaris, psoriatic arthritis, psoriaticepidermis, psychosocial stress diseases, pulmonary disease, pulmonaryfibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenicgranuloma retrolental fibroplasias, pyogenic sterile arthritis,Raynaud's syndrome, Reiter's disease, reactive arthritis, renal disease,renal graft rejection, reperfusion injury, respiratory distresssyndrome, retinal disease, retrolental fibroplasia, Reynaud's syndrome,rheumatic carditis, rheumatic diseases, rheumatic fever, rheumatoidarthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis,Schnitzler syndrome, scleritis, sclerosis, scleroderma, scoliosis,seborrhea, sepsis, septic shock, severe pain, Sdzary syndrome, sicklecell anemia, silica-induced disease (Silicosis), Sjogren's syndrome,skin diseases, skin irritation, skin rash, skin sensitization (contactdermatitis or allergic contact dermatitis), spinal cord injury, spinalstenosis, spondyloarthropathies, Stevens-Johnson syndrome (SJS), stroke,subarachnoid hemorrhage, sunburn, synovial inflammation, systemicinflammatory response syndrome (SIRS), systemic lupus erythematosus,systemic mast cell disease (SMCD), systemic vasculitis, systemic-onsetjuvenile idiopathic arthritis, temporal arteritis, tendinitis,tenosynovitis, thrombocytopenia, thyroditis, thyroiditis, tissuetransplant, toxoplasmosis, trachoma, transplantation rejection,traumatic brain injury, tuberculosis, tubulointerstitial nephritis,tumor necrosis factor (TNF) receptor associated periodic syndrome(TRAPS), type 1 diabetes, type 2 diabetes, complications from type 1 ortype 2 diabetes, ulcerative colitis, urticaria, uterine fibroids,uveitis, uveoretinitis, vascular restenosis, vasculitis, vasculitis(NHLBI), vitiligo, Wegener's granulomatosis, or Whipple disease.

In some embodiments, the autoimmune disease is systemic lupuserythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA), acutedisseminated encephalomyelitis, idiopathic thrombocytopenic purpura,multiple sclerosis (MS), inflammatory bowel disease (IBD), sepsis,psoriasis, Sjoegren's syndrome, autoimmune hemolytic anemia, asthma, orchronic obstructive pulmonary disease (COPD), ankylosing spondylitis,acute gout and ankylosing spondylitis, reactive arthritis, monoarticulararthritis, osteoarthritis, gouty arthritis, juvenile arthritis, juvenileonset rheumatoid arthritis, juvenile rheumatoid arthritis or psoriaticarthritis. In other embodiments, the disease is inflammation. In yetother embodiments, the disease is excessive or destructive immunereactions, such as asthma, rheumatoid arthritis, multiple sclerosis,chronic obstructive pulmonary disease (COPD), and lupus.

In some embodiments, the disease or condition mediated by Cot isinflammatory bowel disease (IBD). The term “inflammatory bowel disease”or “IBD” as used herein is a collective term describing inflammatorydisorders of the gastrointestinal tract, the most common forms of whichare ulcerative colitis and Crohn's disease. Other forms of IBD that canbe treated with the presently disclosed compounds, compositions andmethods include diversion colitis, ischemic colitis, infectious colitis,chemical colitis, microscopic colitis (including collagenous colitis andlymphocytic colitis), atypical colitis, pseudomembranous colitis,fulminant colitis, autistic enterocolitis, indeterminate colitis,Behget's disease, gastroduodenal CD, jejunoileitis, ileitis,ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome,mucositis, radiation induced enteritis, short bowel syndrome, celiacdisease, stomach ulcers, diverticulitis, pouchitis, proctitis, andchronic diarrhea.

Treating or preventing IBD also includes ameliorating or reducing one ormore symptoms of IBD. As used herein, the term “symptoms of IBD” refersto detected symptoms such as abdominal pain, diarrhea, rectal bleeding,weight loss, fever, loss of appetite, and other more seriouscomplications, such as dehydration, anemia and malnutrition. A number ofsuch symptoms are subject to quantitative analysis (e.g. weight loss,fever, anemia, etc.). Some symptoms are readily determined from a bloodtest (e.g. anemia) or a test that detects the presence of blood (e.g.rectal bleeding). The term “wherein said symptoms are reduced” refers toa qualitative or quantitative reduction in detectable symptoms,including but not limited to a detectable impact on the rate of recoveryfrom disease (e.g. rate of weight gain). The diagnosis is typicallydetermined by way of an endoscopic observation of the mucosa, andpathologic examination of endoscopic biopsy specimens.

The course of IBD can vary and can be associated with intermittentperiods of disease remission and disease exacerbation. Various methodshave been described for characterizing disease activity and severity ofIBD as well as response to treatment in subjects having IBD. Treatmentaccording to the present methods are generally applicable to a subjecthaving IBD of any level or degree of disease activity.

In some embodiments, the disease or condition treated by theadministration of a compound of composition described herein includesacute gout and ankylosing spondylitis, allergic disorders, Alzheimer'sdisease, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateralsclerosis and multiple sclerosis, atherosclerosis, bacterial infections,bone cancer pain and pain due to endometriosis, BRAF resistant melanoma,brain stem glioma or pituitary adenomas, burns, bursitis, cancer of theanal region, cancer of the endocrine system, cancer of the kidney orureter (e.g. renal cell carcinoma carcinoma of the renal pelvis), cancerof the penis, cancer of the small intestine, cancer of the thyroid,cancer of the urethra, cancers of the bloodsuch as acute myeloidleukemia, cancers of the tongue, carcinoma of the cervix, carcinoma ofthe endometrium, carcinoma of the fallopian tubes, carcinoma of therenal pelvis, carcinoma of the vagina or carcinoma of the vulva, chronicmueloid leukemia, chronic or acute leukemia, chronic pain, classicBaitter syndrome, common cold conjunctivitis, coronary heart disease,cutaneous or intraocular melanoma, dermatitis, dysmenorrhea, eczema,endometriosis, familial adenomatous polyposis, fibromyalgia, fungalinfections, gout, gynecologic tumors, uterine sarcomas, carcinoma of thefallopian tubes, headache, hemophilic arthropathy, Parkinson's disease,AIDS, herpes zoster, Hodgkin's disease, Huntington's, hyperprostaglandinE syndrome, influenza, iritis, juvenile arthritis, juvenile onsetrheumatoid arthritis, juvenile rheumatoid arthritis, low back and neckpain, lynphocytic lymphomas, myofascial disorders, myositis, neuralgia,neurodegenerative disorders such as Alzheimer's disease,neuroinflammatory disorders, neuropathic pain, carcinoma of the vulva,Parkinson's disease, pediatric malignancy, pulmonary fibrosis rectalcancer, rhinitis, sarcoidosis, sarcomas of soft tissues, scleritis, skincancer, solid tumors of childhood, spinal axis tumors, sprains andstrains, stomach cancer, stroke, subacute and chronic musculoskeletalpain syndromes such as bursitis, surgical or dental procedures, symptomsassociated with influenza or other viral infections, synovitis,toothache, ulcers, uterine cancer, uterine sarcomas, uveitis,vasculitis, viral infections, viral infections {e.g. influenza) andwound healing.

Criteria useful for assessment of disease activity in subjects withulcerative colitis can be found in, e.g., Truelove et al. (1955) Br MedJ 2:1041-1048. Using these criteria, disease activity can becharacterized in a subject having IBD as mild disease activity or severedisease activity. Subjects who do not meet all the criteria for severedisease activity, and who exceed the criteria for mild disease activityare classified as having moderate disease activity.

The presently disclosed treatment methods can also be applied at anypoint in the course of the disease. In certain embodiments, the methodsare applied to a subject having IBD during a time period of remission(i.e., inactive disease). In such embodiments, the present methodsprovide benefit by extending the time period of remission (e.g.,extending the period of inactive disease) or by preventing, reducing, ordelaying the onset of active disease. In other embodiments, methods maybe applied to a subject having IBD during a period of active disease.Such methods provide benefit by reducing the duration of the period ofactive disease, reducing or ameliorating one or more symptoms of IBD, ortreating IBD.

Measures for determining efficacy of treatment of IBD in clinicalpractice have been described and include, for example, the following:symptom control; fistula closure; extent of corticosteroid therapyrequired; and, improvement in quality of life. Heath-related quality oflife (HRQL) can be assessed using the Inflammatory Bowel DiseaseQuestionnaire (IBDQ), which is extensively used in clinical practice toassess quality of life in a subject with IBD. (See Guyatt et al. (1989)Gastroenterology 96:804-810.) In some embodiments, the disease orcondition is immune-mediated liver injury, disease or condition. Tpl2can mediate immune related liver diseases or conditions. (Vyrla et. al.,The Journal of Immunology, 2016, 196; Perugorria et. al., Hepatology,2013; 57:1238-1249).

In some embodiments, the disease or condition mediated by Cot isalcoholic hepatitis. Alcoholic hepatitis is a clinical syndromecharacterized by jaundice and liver failure that develops in subjectswith chronic and active alcohol abuse. (See Akriviadis E. et. al, AnnGastroenterol. 2016 April-June; 29(2): 236-237). Alcoholic hepatitis cancause cirrhosis and fibrosis of the liver cells. Glucocorticoids, (e.g.prednisolone) and phosophodiesterase inhibitors (e.g. pentoxifylline)can be used to treat alcoholic hepatitis. The compounds herein can beused as stand-alone treatments or in combination with the currenttreatments for alcoholic hepatitis.

In some embodiments, the disease or condition mediated by Cot issystemic lupus erythematosus (SLE), lupus nephritis, lupus-related, orother autoimmune disorders or a symptom of SLE. Symptoms of systemiclupus erythematosus include joint pain, joint swelling, arthritis,fatigue, hair loss, mouth sores, swollen lymph nodes, sensitivity tosunlight, skin rash, headaches, numbness, tingling, seizures, visionproblems, personality changes, abdominal pain, nausea, vomiting,abnormal heart rhythms, coughing up blood and difficulty breathing,patchy skin color and Raynaud's phenomenon.

In some embodiments, the disease or condition mediated by Cot is acuteor chronic liver failure, acute intrahepatic cholestatic conditions, ofobstructive or chronic inflammatory disorders that arise out of improperbile composition, alcohol-induced cirrhosis and associated cholestasis,a cholestatic or fibrotic effect that is associated with alcohol-inducedcirrhosis or with a viral-borne form of hepatitis, chemotherapyassociated steatohepatitis (CASH), chronic intrahepatic or extrahepaticcholestatic condition, a chronic or obstructive inflammatory disorder ofthe liver, congential hepatic fibrosis, a lipid disorder or lipoproteindisorder, liver fibrosis, liver cirrhosis, liver failure or liverischemia after major liver resection, liver steatosis or an associatedsyndrome, liver ischemia after major liver resection, a neoplasticdiease of the gastrointestinal tract or liver, Non-Alcoholic Fatty LiverDisease (NAFLD), Non-Alcoholic Steatohepatitis (NASH), obstructive orchronic inflammatory disorders of the liver, obesity, Primary BiliaryCirrhosis (PBC), Primary Sclerosing Cholangitis (PSC), progressivefamiliar cholestatsis, or a metabolic syndrome selected from the groupconsisting of combined conditions of dyslipidemia, diabetes andabnormally high body-mass index.

In some embodimetns, the diease or condition mediated by Cot is diabetickidney disease (DKD).

Improvements in any of the foregoing response criteria are specificallyprovided by the methods of the present disclosure.

Combination Therapies

In one embodiment, the compounds disclosed herein may be used incombination with one or more additional therapeutic agents.

In some embodiments, the additional therapeutic agent(s) are being usedand/or developed to treat inflammatory disorders (e.g., IBD). The one ormore additional therapeutic agents may be Beta adrenoceptor antagonists,Beta-glucuronidase inhibitors, Bradykinin receptor modulators,Calcineurin inhibitors, Calcium channel inhibitors, Cathepsin Sinhibitors, CCR3 chemokine antagonists, CD40 ligand receptorantagonists, Chemokine CXC ligand inhibitors, CHST15 gene inhibitors,Collagen modulators, CSF-1 antagonists, Cyclooxygenase inhibitors,Cytochrome P450 3A4 inhibitors, Eotaxin ligand inhibitors, EP4prostanoid receptor agonists, Fractalkine ligand inhibitors, Free fattyacid receptor 2 antagonists, GATA 3 transcription factor inhibitors,Glucagon-like peptide 2 agonists, Glucocorticoid agonists, Guanylatecyclase receptor agonists, Histone deacetylase inhibitors, HLA class IIantigen modulators, IL-12 antagonists, IL-13 antagonists, IL-23antagonists, IL-6 antagonists, IL-6 receptor modulators, interleukin-7receptor modulators, IL-7 antagonists, IL-8 antagonists, Integrinalpha-4/beta-1 antagonists, Integrin alpha-4/beta-7 antagonists,Integrin alpha-E antagonists, Integrin antagonists, Integrin beta-7antagonists, Interleukin ligand inhibitors, Interleukin receptor 17Aantagonists, Interleukin-1 beta ligands, Interleukin-1 beta ligandmodulators, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinaseinhibitors, Jak3 tyrosine kinase inhibitors, LanC like protein 2modulators, Lipoxygenase modulators, MAdCAM inhibitors, Matrixmetalloprotease inhibitors, Melanocortin agonists, Metalloprotease-9inhibitors, Natriuretic peptide receptor C agonists, Neuregulin-4ligands, NKG2 D activating NK receptor antagonists, Opioid receptorantagonists, Opioid receptor delta antagonists, Oxidoreductaseinhibitors, P2X7 purinoceptor agonists, PDE 4 inhibitors, Phagocytosisstimulating peptide modulators, Potassium channel inhibitors, PPAR alphaagonists, PPAR delta agonists, PPAR gamma agonists, Protein fimHinhibitors, P-selectin glycoprotein ligand-1 inhibitors, RNA polymeraseinhibitors, Sphingosine 1 phosphate phosphatase 1 stimulators,Sphingosine 1 phosphate phosphatase modulators, Sphingosine-1-phosphatereceptor-1 agonists, Sphingosine-1-phosphate receptor-1 antagonists,Sphingosine-1-phosphate receptor-1 modulators, Sphingosine-1-phosphatereceptor-5 modulators, STAT3 gene inhibitors, Stem cell antigen-1inhibitors, Superoxide dismutase modulators, Superoxide dismutasestimulators, TGF beta 1 ligand inhibitors, thymulin agonists, TLRantagonists, TLR agonists, TNF alpha ligand inhibitors, TNF antagonists,Tumor necrosis factor 14 ligand modulators, Type II TNF receptormodulators, Zonulin inhibitors.

Exemplary additional therapeutic agents include ABX-464, adalimumab;alicaforsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast; Alequel;AMG-139; amiselimod, ASD-003, ASP-3291, AX-1505, BBT-401, balsalazide;beclomethasone dipropionate; BI-655130, BMS-986184; budesonide; CEQ-508;certolizumab; Clostridium butyricum; ChAdOx2-HAV, dexamethasone sodiumphosphate, DNVX-078, etanercept; ETX-201, golimumab; infliximab;mesalazine, HLD-400, LYC-30937 EC; IONIS-JBI1-2.5Rx, JNJ-64304500,naltrexone; natalizumab; neihulizumab, olsalazine; PH-46-A,propionyl-L-camitine; PTG-100; remestemcel-L; tacrolimus; teduglutide;tofacitinib; ASP-1002; ustekinumab; vedolizumab; AVX-470; INN-108;SGM-1019; PF-06480605; PF-06651600; PF-06687234; RBX-8225, SER-287;Thetanix; TOP-1288; VBY-129; 99mTc-annexin V-128; bertilimumab; DLX-105;dolcanatide; E-6011; FFP-104; filgotinib; foralumab; GED-0507-34-Levo;givinostat; GLPG-0974; iberogast; JNJ-40346527; K(D)PT; KAG-308;KHK-4083; KRP-203; larazotide acetate; LY-3074828, midismase;olokizumab; OvaSave; P-28-GST; PF-547659; prednisolone; QBECO; RBX-2660,JKB-122; SB-012; STNM-01; Debio-0512; TRK-170; zucapsaicin; ABT-494;Ampion; B1-655066; carotegast methyl; cobitolimod; elafibranor;etrolizumab; GS-5745; HMPL-004; LP-02, ozanimod; peficitinib; RHB-104;rifaximin; tildrakizumab; tralokinumab; brodalumab; laquinimod;plecanatide; or AZD-058.

In some embodiments, the additional thereapeutic agent(s) includes oneor more Alpha-fetoprotein modulator, such as ACT-101; Beta adrenoceptorantagonists, such as NM-001; Calcineurin inhibitors, such as tacrolimus;Carbohydrate metabolism modulators, such as ASD-003; Cathepsin Sinhibitors, such as VBY-129; CD40 ligand receptor antagonists, such asFFP-104, BI-655064; Chemokine CXC ligand inhibitors, such as LY-3041658;CHST15 gene inhibitors, such as STNM-01; Collagen modulators, such asECCS-50 (DCCT-10); CSF-1 antagonists, such as JNJ-40346527 (PRV-6527);CX3CR1 chemokine modulator, such as E-6130; Ecobiotic, such as SER-287;Eotaxin ligand inhibitors, such as bertilimumab; EP4 prostanoid receptoragonists, such as KAG-308; FIFO ATP synthase modulator, such asLYC-30937 EC; Fractalkine ligand inhibitors, such as E-6011; Free fattyacid receptor 2 antagonists, such as GLPG-0974; GATA 3 transcriptionfactor inhibitors, such as SB-012; Glucagon-like peptide 2 agonists,such as teduglutide; Glucocorticoid agonists, such as budesonide,beclomethasone dipropionate, dexamethasone sodium phosphate; Guanylatecyclase receptor agonists, such as dolcanatide; HIF prolyl hydroxylaseinhibitor, such as DS-1093, AKB-4924; Histone deacetylase inhibitors,such as givinostat; HLA class II antigen modulators, such as HLA classII protein modulators; IL-12 antagonists, such as ustekinumab(IL12/IL23); IL-13 antagonists, such as tralokinumab; IL-22 agonists,such as RG-7880; IL-23 antagonists, such as tildrakizumab, risankizumab(B1-655066), mirikizumab (LY-3074828), brazikumab (AMG-139), PGT-200;IL-6 antagonists, such as olokizumab; IL-8 receptor antagonists, such asclotrimazole; Integrin alpha-4/beta-1 antagonists, such as natalizumab;Integrin alpha-4/beta-7 antagonists, such as etrolizumab (α4β7/αEβ7),vedolizumab, carotegast methyl, TRK-170 (α4β7/α4β1), PTG-100; Integrinantagonists, such as E-6007; Interleukin ligand inhibitors, such asbimekizumab (IL-17A/IL-17E); Interleukin receptor 17A antagonists, suchas brodalumab; Interleukin-1 beta ligands, such as K(D)PT; Interleukin 1like receptor 2 inhibitor, such as BI-655130; IL-6 receptor modulator,such as olamkicept; JAK tyrosine kinase inhibitors, such as tofacitinib(1/3), peficitinib (1/3), TD-3504, TD-1473; Jak1 tyrosine kinaseinhibitors, such as upadacitinib (ABT-494), filgotinib, GLPG-0555,PF-06700841 (JAK1/Tyk2); Jak3 tyrosine kinase inhibitors, such asPF-06651600; LanC like protein 2 modulators, such as BT-11; MAdCAMinhibitors, such as SHP-647 (PF-547659); melanin concentrating hormone(MCH-1) antagonist, such as CSTI-100; Melanocortin agonists, such asASP-3291, PL-8177; Metalloprotease-9 inhibitors, such as GS-5745;Natriuretic peptide receptor C agonists, such as plecanatide;Neuregulin-4 ligands, such as NRG-4; NKG2 D activating NK receptorantagonists, such as JNJ-4500; Opioid receptor antagonists, such asnaltrexone, IRT-103; OX40 ligand inhibitor, such as KHK-4083;Oxidoreductase inhibitors, such as olsalazine; P2X7 purinoceptormodulator, such as SGM-1019; PDE 4 inhibitors, such as apremilast; PPARalpha/delta agonists, such as elafibranor (GFT-1007); PPAR gammaagonists, such as GED-0507-34-Levo; Protein fimH inhibitors, such asEB-8018; P-selectin glycoprotein ligand-1 inhibitors, such as SEL-K2,neihulizumab; Ret tyrosine kinase receptor inhibitor, such asGSK-3179106; RIP-1 kinase inhibitor, such as GSK-2982772; RIP-2 kinaseinhibitor, such as GSK-2983559; Sphingosine 1 phosphate phosphatase 1stimulators, such as etrasimod; Sphingosine-1-phosphate receptor-1agonists, such as ozanimod, mocravimod (KRP-203), BMS-986166;Sphingosine-1-phosphate receptor-1 antagonists, such as amiselimod(MT-1303); Stem cell antigen-1 inhibitors, such as Ampion (DMI-9523);Superoxide dismutase modulators, such as midismase; TLR-4 antagonists,such as JKB-122; TLR-9 agonists, such as cobitolimod; TNF alpha ligandinhibitors, such as adalimumab, certolizumab, infliximab, golimumab,DLX-105, Debio-0512, HMPL-004, CYT-020-TNFQb, V-565; TNF antagonists,such as AVX-470, tulinercept, etanercept; TPL-2 inhibitor, such asGS-4875; Tumor necrosis factor 14 ligand modulators, such as AEVI-002;Tumor necrosis factor 15 ligand inhibitor, such as PF-06480605; TypeIIL-1 receptor antagonist, such as anakinra; and/or Zonulin inhibitors,such as larazotide acetate.

In some embodiments, the one or more additional therapeutic agent may bea α4β7 integrin inhibitor, or an agent that inhibits the expressionand/or activity of α4β7 integrin. The inhibitor can be small molecule orbiologic. For example, the α4β7 integrin inhibitor can be natalizumab orvedolizumab.

In some embodiments, the one or more additional therapeutic agent may bea steroid, including but not limited to, corticosteroids.Corticosteroids may be administered by various routes, includingintravenously (i.e., methylprednisolone, hydrocortisone), orally (i.e.,prednisone, prednisolone, budesonide, dexamethasone), or topically(i.e., enema, suppository, or foam preparations).

In some embodiments, the one or more additional therapeutic agent may bean MMP9 inhibitor, or an agent that inhibits the expression and/oractivity of MMP9. A representative protein sequence for MMP9 is GenBankAccession No. NP_004985. The inhibitor can be small molecule orbiologic. For instance, Gu et al., The Journal of Neuroscience, 25(27):6401-6408 (2005) discloses a specific MMP9 inhibitor, SB-3CT (CAS292605-14-2). Further, siRNA, antisense RNA and antibodies have alsobeen demonstrated to inhibit the expression or activity of MMP9 and arewithin the scope of the present disclosure. In one embodiment, an MMP9inhibitor is a monoclonal anti-MMP9 antibody. In some embodiment, theone or more additional therapeutic agent includes an MMP9 inhibitor anda nucleoside analog such as gemcitabine.

In some embodiments, the one or more additional therapeutic agent may bea Sphingosine 1-Phosphate Receptor (SIPI) inhibitor, or an agent thatinhibits the expression and/or activity of S1P1. The inhibitor can besmall molecule or biologic. For example, the S1P1 inhibitor can beRPC1063.

In some embodiments, the one or more additional therapeutic agent may bea TNF inhibitor, or an agent that inhibits the expression and/oractivity of TNF. The inhibitor can be small molecule or biologic. Forexample, the TNF inhibitor can be golimumab.

In some embodiments, the one or more additional therapeutic agent isbeing used and/or developed to treat ulcerative colitis (UC) and/orCrohn disease (CD). The agent can be a biologic or small molecule. Insome embodiments, the agent is a modulator (e.g., agonist or antagonist)of alpha-fetoprotein, beta adrenoceptor, calcineurin, carbohydratemetabolism, cathepsin S, S1P1, IL-6, CX3CL1, DHODH, α4, β7, JAK, TNF,CB, IL-12/IL-23, CCL20, TLR9, MAdCAM, CCR9, CXCL10, Smad7, PDE4, MC,VLA-1, GC, GATA-3, Eotaxin, FFA2, LIGHT, FMS, MMP9, CD40, Steroid,5-ASA, Immunomod, STAT3, and/or EP4.

In some embodiments the additional therapeutic agent(s) are being usedand/or developed to treat IBD. Non-limiting examples of agents beingused and/or developed to treat IBD include ABX-464, adalimumab;alicaforsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast; Alequel;AMG-139; amiselimod, ASD-003, ASP-3291, AX-1505, BBT-401, balsalazide;beclomethasone dipropionate; BI-655130, BMS-986184; budesonide; CEQ-508;certolizumab; Clostridium butyricum; ChAdOx2-HAV, dexamethasone sodiumphosphate, DNVX-078, etanercept; ETX-201, golimumab; infliximab;mesalazine, HLD-400, LYC-30937 EC; IONIS-JBI1-2.5Rx, JNJ-64304500,naltrexone; natalizumab; neihulizumab, olsalazine; PH-46-A,propionyl-L-camitine; PTG-100; remestemcel-L; tacrolimus; teduglutide;tofacitinib; ASP-1002; ustekinumab; vedolizumab; AVX-470; INN-108;SGM-1019; PF-06480605; PF-06651600; PF-06687234; RBX-8225, SER-287;Thetanix; TOP-1288; VBY-129; 99mTc-annexin V-128; bertilimumab; DLX-105;dolcanatide; E-6011; FFP-104; filgotinib; foralumab; GED-0507-34-Levo;givinostat; GLPG-0974; iberogast; JNJ-40346527; K(D)PT; KAG-308;KHK-4083; KRP-203; larazotide acetate; LY-3074828, midismase;olokizumab; OvaSave; P-28-GST; PF-547659; prednisolone; QBECO; RBX-2660,JKB-122; SB-012; STNM-01; Debio-0512; TRK-170; zucapsaicin; ABT-494;Ampion; BI-655066; carotegast methyl; cobitolimod; elafibranor;etrolizumab; GS-5745; HMPL-004; LP-02, ozanimod; peficitinib; RHB-104;rifaximin; tildrakizumab; tralokinumab; brodalumab; laquinimod;plecanatide; and AZD-058.

Non-limiting examples of agents being used and/or developed to treatulcerative colitis (UC) and Crohn disease (CD) include PF-06410293 (byPfizer), SAN-300 (VLA-1 modulator, by Salix), SAR252067 (LIGHTmodualtor, by Sanofi), PF-00547659 (MAdCAM modualtor, by Pfizer),Eldelumab (Smad7 modulator, by BMS), AMG 181/MEDI-7183 (07 modulator, byAmgen/AstraZeneca), Etrolizumab (07 modulator, by Roche), Ustekinumab(IL-12/IL-23 modulator, by J&J), Remicade (TNF modulator, by J&J andMerck), Entyvio (07 modulator, by Takeda), Humira (TNF modulator, byAbbvie), Infliximab (by Celtrion), PF-06651600 (by Pfizer), GSK2982772(by GSK), GLPG1205 (FFA2 modulator, by Galapagos), AG014 (by Intrexon)and Vidofludimus (DHODH modulator, by 4SC).

In some embodiments, the one or more additional therapeutic agent may bea JAK inhibitor, such as a JAK-1 selective inhibitor. The inhibitor canbe small molecule or biologic. For example, the JAK inhibitor can beFilgotinib, GLPG0634 (JAK modulator, by Galápagos).

In some embodiments, the one or more additional therapeutic agentsis/are a(n) ACE inhibitor, Acetaldehyde dehydrogenase inhibitor, AcetylCoA carboxylase inhibitor, Acetyl CoA carboxylase inhibitor,Diacylglycerol O acyltransferase 2 inhibitor, Adenosine A3 receptoragonist, Adiponectin receptor agonist, Aldehyde dehydrogenase 2stimulator, AKT protein kinase inhibitor, AMP-activated protein kinases(AMPK), AMP kinase activator, ATP citrate lyase inhibitor, AMP activatedprotein kinase stimulator, Endothelial nitric oxide synthase stimulator,NAD-dependent deacetylase sirtuin-1 stimulator, Androgen receptoragonist, Amylin receptor agonist, Angiotensin IIAT-1 receptorantagonist, Autophagy protein modulator, Autotaxin inhibitors, Axltyrosine kinase receptor inhibitor, Bax protein stimulator, Bioactivelipid, Calcitonin agonist, Cannabinoid receptor modulator, Caspaseinhibitor, Caspase-3 stimulator, Cathepsin inhibitor, Caveolin 1inhibitor, CCR2 chemokine antagonist, CCR2 chemokine antagonist,Angiotensin II AT-1 receptor antagonist, CCR3 chemokine antagonist, CCR5chemokine antagonist, CD3 antagonist, Chloride channel stimulator, CNR1inhibitor, Cyclin D1 inhibitor, Cytochrome P450 7A1 inhibitor, DGAT1/2inhibitor, Diacylglycerol O acyltransferase 1 inhibitor (DGAT1),Cytochrome P450 2E1 inhibitor (CYP2E1), CXCR4 chemokine antagonist,Dipeptidyl peptidase IV inhibitor, Endosialin modulator, Eotaxin ligandinhibitor, Extracellular matrix protein modulator, Famesoid X receptoragonist, Fatty acid synthase inhibitors, FGF1 receptor agonist,Fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligands, Galectin-3inhibitor, Glucagon receptor agonist, Glucagon-like peptide 1 agonist,G-protein coupled bile acid receptor 1 agonist, G-protein coupledreceptor 84 antagonist, Hedgehog (Hh) modulator, Hepatitis C virus NS3protease inhibitor, Hepatocyte nuclear factor 4 alpha modulator (HNF4A),Hepatocyte growth factor modulator, Histone deacetylase inhibitor,STAT-3 modulator, HMG CoA reductase inhibitor, Hypoxia induciblefactor-2 alpha inhibitor, IL-10 agonist, IL-17 antagonist, Ileal sodiumbile acid cotransporter inhibitor, Insulin sensitizer, Insulin ligandagonist, Insulin receptor agonist, integrin modulator, IntegrinAntagonist, intereukin-1 receptor-associated kinase 4 (IRAK4) inhibitor,IL-6 receptor agonist, Jak2 tyrosine kinase inhibitor, Ketohexokinase(KHK) inhibitor, Klotho beta stimulator, 5-Lipoxygenase inhibitor,Lipoprotein lipase inhibitor, Liver X receptor, LPL gene stimulator,Lysophosphatidate-1 receptor antagonist, Lysyl oxidase homolog 2inhibitor, Macrophage mannose receptor 1 modulator, Matrixmetalloproteinases (MMPs) inhibitor, MEKK-5 protein kinase inhibitor,MCH receptor-1 antagonist, Membrane copper amine oxidase (VAP-1)inhibitor, Methionine aminopeptidase-2 inhibitor, Methyl CpG bindingprotein 2 modulator, MicroRNA-21 (miR-21) inhibitor, Mitochondrialuncoupler, Mixed lineage kinase-3 inhibitor, Myelin basic proteinstimulator, NACHT LRR PYD domain protein 3 (NLRP3) inhibitor,NAD-dependent deacetylase sirtuin stimulator, NADPH oxidase inhibitor(NOX), Nicotinic acid receptor 1 agonist, P2Y13 purinoceptor stimulator,Nuclear receptor modulators, P2X7 purinoceptor modulator, PDE 3inhibitor, PDE 4 inhibitor, PDE 5 inhibitor, PDGF receptor betamodulator, Phenylalanine hydroxylase stimulator, Phospholipase Cinhibitor, PPAR alpha agonist, PPAR delta agonist, PPAR gamma agonist,Peptidyl-prolyl cis-trans isomerase A inhibitor, PPAR gamma modulator,Protease-activated receptor-2 antagonist, Protein kinase modulator, Rhoassociated protein kinase inhibitor, Snitrosoglutathione reductase(GSNOR) enzyme inhibitor, Sodium glucose transporter-2 inhibitor, SREBPtranscription factor inhibitor, STAT-1 inhibitor, Stearoyl CoAdesaturase-1 inhibitor, STK25 inhibitor, Suppressor of cytokinesignalling-1 stimulator, Suppressor of cytokine signalling-3 stimulator,Transforming growth factor β (TGF-β), Transforming growth factor βactivated Kinase 1 (TAK1), Thyroid hormone receptor beta agonist, TLR-4antagonist, Transglutaminase inhibitor, Tyrosine kinase receptormodulator, GPCR modulator, nuclear hormone receptor modulator, WNTmodulators, or YAP/TAZ modulator and Zonulin inhibitor.

For example, the additional therapeutic agent(s) may include A-4250,AC-3174, acetylsalicylic acid, AK-20, alipogene tiparvovec, AMX-342,AN-3015, aramchol, ARI-3037MO, ASP-8232, AZD-2693, bertilimumab, Betaineanhydrous, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191,BTT-1023, CAT-2003, cenicriviroc, CBW-511, CER-209, CF-102, CGS21680,CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam,dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer,2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elafibranor(GFT-505), emricasan, enalapril, ertugliflozin, evogliptin, F-351,fluasterone (ST-002), FT-4101, GKT-831, GNF-5120, GRI-0621, GR-MD-02,GS-300, GS-4997, GS-9674, HTD-1801, HST-202, HST-201,hydrochlorothiazide, icosabutate (PRC-4016), icosapent ethyl ester,IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, ipragliflozin, Irbesarta,propagermanium, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790,M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide,UN-452, LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MBX-8025,MDV-4463, mercaptamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K,namacizumab, NC-101, NDI-010976, ND-L02-s0201, NGM-282, NGM-313,NGM-386, NGM-395, NP-160, norursodeoxycholic acid, NVP-022, O-304,obeticholic acid, 25HC3S, olesoxime, PAT-505, PAT-048, PB-4547,peg-ilodecakin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102,PX-L603, PX-L493, PXS-4728A, PZ-235, RDX-009, remogliflozin etabonate,RG-125 (AZD4076), RPI-500, saroglitazar, semaglutide, simtuzumab,solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin,pitavastatin, pravastatin, rosuvastatin, simvastatin), TCM-606F,TEV-45478, TQA-3526, tipelukast (MN-001), TLY-012, TRX-318, TVB-2640,UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, vismodegib,volixibat potassium ethanolate hydrate (SHP-626), VVP-100X, WAV-301,WNT-974, XRx-117, ZGN-839, ZG-5216, ZSYM-008, ZYSM-007.

Kits

Provided herein are also kits that include a compound described herein,or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixtureof stereoisomers, prodrug, or deuterated analog thereof, and suitablepackaging. In one embodiment, a kit further includes instructions foruse. In one aspect, a kit includes a compound of Formula I (or any otherFormula described herein), or a pharmaceutically acceptable salt,tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuteratedanalog thereof, and a label and/or instructions for use of the compoundsin the treatment of the indications, including the diseases orconditions, described herein.

Provided herein are also articles of manufacture that include a compounddescribed herein or a pharmaceutically acceptable salt, tautomer,stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogthereof in a suitable container. The container may be a vial, jar,ampoule, preloaded syringe, and intravenous bag.

Pharmaceutical Compositions and Modes 0/Administration

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provided herein are alsopharmaceutical compositions that contain one or more of the compoundsdescribed herein or a pharmaceutically acceptable salt, tautomer,stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogthereof and one or more pharmaceutically acceptable vehicles selectedfrom carriers, adjuvants and excipients. Suitable pharmaceuticallyacceptable vehicles may include, for example, inert solid diluents andfillers, diluents, including sterile aqueous solution and variousorganic solvents, permeation enhancers, solubilizers and adjuvants. Suchcompositions are prepared in a manner well known in the pharmaceuticalart. See, e.g., Remington's Pharmaceutical Sciences, Mace PublishingCo., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, MarcelDekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical composition may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In certain embodiments, the pharmaceuticalcomposition may be administered by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds described herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound described herein or apharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof, the activeingredient is usually diluted by an excipient and/or enclosed withinsuch a carrier that can be in the form of a capsule, sachet, paper orother container. When the excipient serves as a diluent, it can be inthe form of a solid, semi-solid, or liquid material, which acts as avehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, sterile injectable solutions, and sterile packagedpowders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions that include at least one compound described herein ora pharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof can be formulatedso as to provide quick, sustained or delayed release of the activeingredient after administration to the subject by employing proceduresknown in the art. Controlled release drug delivery systems for oraladministration include osmotic pump systems and dissolutional systemscontaining polymer-coated reservoirs or drug-polymer matrixformulations. Examples of controlled release systems are given in U.S.Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Anotherformulation for use in the methods disclosed herein employ transdermaldelivery devices (“patches”). Such transdermal patches may be used toprovide continuous or discontinuous infusion of the compounds describedherein in controlled amounts. The construction and use of transdermalpatches for the delivery of pharmaceutical agents is well known in theart. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein or a pharmaceutically acceptable salt,tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuteratedanalog thereof. When referring to these preformulation compositions ashomogeneous, the active ingredient may be dispersed evenly throughoutthe composition so that the composition may be readily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation may include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedherein. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect. In otherembodiments, compositions in pharmaceutically acceptable solvents may benebulized by use of inert gases. Nebulized solutions may be inhaleddirectly from the nebulizing device or the nebulizing device may beattached to a facemask tent, or intermittent positive pressure breathingmachine. Solution, suspension, or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

Dosing

The specific dose level of a compound of the present application for anygiven subject will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the given disease in the subject undergoing therapy. For example, adosage may be expressed as a number of milligrams of a compounddescribed herein per kilogram of the subject's body weight (mg/kg).Dosages of between about 0.1 and 150 mg/kg may be appropriate. In someembodiments, about 0.1 and 100 mg/kg may be appropriate. In otherembodiments a dosage of between 0.5 and 60 mg/kg may be appropriate.Normalizing according to the subject's body weight can be useful whenadjusting dosages between subjects of widely disparate size, such asoccurs when using the drug in both children and adult humans or whenconverting an effective dosage in a non-human subject such as dog to adosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compounddescribed herein administered per dose or per day. Daily dosage of acompound of Formula I may be between about 1 mg and 4,000 mg, betweenabout 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, betweenabout 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to200 mg/day, or between about 15 to 150 mg/day. In some embodiments, acompound a daily dosage of a compound of Formula I, or another formuladescribed herein, is between about 150 mg/day and 1000 mg/day.

When administered orally, the total daily dosage for a human subject maybe between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, betweenabout 10-500 mg/day, between about 50-300 mg/day, between about 75-200mg/day, or between about 100-150 mg/day.

The compounds of the present application or the compositions thereof maybe administered once, twice, three, or four times daily, using anysuitable mode described above. Also, administration or treatment withthe compounds may be continued for a number of days; for example,commonly treatment would continue for at least 7 days, 14 days, or 28days, for one cycle of treatment. Treatment cycles are well known incancer chemotherapy and are frequently alternated with resting periodsof about 1 to 28 days, commonly about 7 days or about 14 days, betweencycles. The treatment cycles, in other embodiments, may also becontinuous.

In some embodiments, the method comprises administering to the subjectan initial daily dose of about 1 to 800 mg of a compound describedherein and increasing the dose by increments until clinical efficacy isachieved. Increments of about 5, 10, 25, 50, or 100 mg can be used toincrease the dose. The dosage can be increased daily, every other day,twice per week, or once per week.

Synthesis of Compounds

Compounds disclosed herein may be prepared using the methods disclosedherein and routine modifications thereof, which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of typical compounds described hereinmay be accomplished as described in the following examples. Ifavailable, reagents may be purchased commercially, e.g., from SigmaAldrich or other chemical suppliers.

General Synthesis

Typical embodiments of compounds described herein may be synthesizedusing the general reaction schemes described below. It will be apparentgiven the description herein that the general schemes may be altered bysubstitution of the starting materials with other materials havingsimilar structures to result in products that are correspondinglydifferent. Descriptions of syntheses follow to provide numerous examplesof how the starting materials may vary to provide correspondingproducts. Given a desired product for which the substituent groups aredefined, the necessary starting materials generally may be determined byinspection. Starting materials are typically obtained from commercialsources or synthesized using published methods. For synthesizingcompounds which are embodiments described in the present disclosure,inspection of the structure of the compound to be synthesized willprovide the identity of each substituent group. The identity of thefinal product will generally render apparent the identity of thenecessary starting materials by a simple process of inspection, giventhe examples herein. In general, compounds described herein aretypically stable and isolatable at room temperature and pressure.

Synthetic Reaction Parameters

The compounds of this disclosure can be prepared from readily availablestarting materials using, for example, the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the specified reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting certain functional groups arewell known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts (1999) Protecting Groups inOrganic Synthesis, 3rd Edition, Wiley, New York, and references citedtherein.

Furthermore, the compounds of this disclosure may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis disclosure, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5, and Supplemental (Elsevier Science Publishers, 1989)organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989).

The term “solvent” generally refers to a solvent inert under theconditions of the reaction being described in conjunction therewith(including, for example, benzene, toluene, acetonitrile, tetrahydrofuran(THF), dimethylformamide (DMF), chloroform, methylene chloride (ordichloromethane), diethyl ether, methanol, and the like). Unlessspecified to the contrary, the solvents are inert organic solvents, andthe reactions may carried out under an inert gas, preferably argon ornitrogen.

The term “q.s.” means adding a quantity sufficient to achieve a statedfunction, e.g., to bring a solution to the desired volume (i.e., 100%).

Compounds of Formula I can be prepared by first providing a substitutedquinoline core, and optionally further modifying the core as desired toprovide the substituents disclosed herein. Scheme 1 shows thepreparation of a quinoline core to provide compounds of Formula 1-e,where m, R⁵ and R¹⁵ are as defined herein, or are a functional groupthat can be converted thereto using standard reaction conditions.

In Scheme 1, suitably substituted 1-a and 1-b are condensed in asuitable solvent (e.g., DMF, etc.) in the presence of catalyst (e.g.,Cs₂CO₃, etc.) at an elevated temperature (e.g., about 40-50° C.) toprovide 1-c. Compound 1-c is then converted to 1-d under thermalcyclization conditions (i.e., about 250° C.) or under microwaveconditions. Chlorination of 1-d to provide 1-e is achieved using asuitable chlorinating agent (e.g., POCl₃, SOCl₂, etc.) at an elevatedtemperature (e.g., about 110-120° C.) in the presence of a base (e.g.pyridine, dimethylaniline, diethylaniline, etc.) or a catalyst (e.g.,DMF, DEF, etc.) and in a suitable solvent (e.g. chlorobenzene, CH₃CN,etc.) or solvent-free conditions (i.e., neat).

Scheme 2 shows a synthesis of compounds of Formula 2-c and 2-d where m,R¹, R², R⁵ and R¹⁵ are as defined herein.

In Scheme 2,1-e is reacted with a suitable amine under standardnucleophilic aromatic substitution conditions in the presence of a base(e.g., NEt₃, etc.) and at elevated temperature (e.g., 150° C.) to obtain2-a. Compounds of Formula I where R⁵ and/or R¹⁵ is cyano are provided byreacting 2-a with a suitable cyanating agent (e.g., CuCN, Zn(CN)₂, etc.)in the presence of a catalyst (e.g., palladium, nickel, copper, etc.).Compounds 2-c and 2-d are then provided via reduction of the nitro groupof compounds 2-a or 2-b, respectively (using e.g., Fe, SnCl₂, etc.).

Scheme 3 shows the synthesis of compounds 3-d and 3-e, where R⁴ is asdefined herein.

In Scheme 3, deuterated 3-c is provided by reducing suitably substitutedaldehyde 3-a with a deuteride-containing reducing agent (e.g., NaBD₄),followed by oxidation of 3-b to the corresponding aldehyde 3-c understandard oxidizing conditions (e.g., MnO₂, Fe₂O₃, NiO, CuO, ZnO, ZrO₂,La₂O₃, Sm₂O₃, Eu₂O₃, Yb₂O₃, etc.). Compound 3-d is obtained in two stepsby reaction of 3-c with ethynyl Grignard, followed by acylation of theresulting alcohol with acetic anhydride in the presence of a base (e.g.,pyridine, TEA, etc.). Compound 3-e is provided in a similar two-stepprocess by reacting suitably substituted aldehyde 3-a with ethynylGrignard, followed by acylation of the resulting alcohol with aceticanhydride.

Scheme 4 shows a synthesis of suitably protected azide compounds ofFormula 4-b, where Lg is a leaving group and R^(3a) is as definedherein.

In Scheme 4, suitably substituted amine 4-a is treated with a diazotransfer agent (e.g., imidazole-1-sulfonyl azide hydrochloride) toafford corresponding 4-b. Alternatively, 4-b may be obtained in twosteps from alcohol 4-c by conversion of the hydroxyl moiety to asuitable leaving group (Lg) (e.g., TsO-, MsO-, NsO-, TfD-, etc.)followed by nucleophilic displacement with azide.

Scheme 5 shows a synthesis of intermediate compounds of Formula 5-c,where R⁵⁰ is alkyl and R^(3a) is as defined herein.

In Scheme 5, suitably substituted triazole 5-b is obtained by reactionof 4-b with 5-a using standard 1,3-dipolar cycloaddition conditions.Acetal 5-b is converted to the corresponding aldehyde 5-c under standardcarbonyl deprotection conditions (e.g., aqueous acid).

Scheme 6 shows an exemplary synthesis of compounds of 6b and 6c, whereR^(3a), m, R¹, R², R⁴, R⁵ and R¹⁵ are as defined herein.

In Scheme 6, compounds of Formula 6-c can be provided via N-alkylationof amine 2-d with 3-d (or 3-e), followed by cyclization with azide 4-bunder standard 1,3-dipolar cycloaddition conditions. Separation of theisomers of Formula 6-a to give compounds of Formula 6-b can be performedusing standard chiral separation/resolution techniques (e.g., chiralchromatography, crystallization, etc.). Alternatively, compounds ofFormula 6-b can be provided via enantioselective N-alkylation of 2-dwith 3-d (or 3-e) using a chiral metal complex (e.g., [Cu(CH₃CN)₄]PF₆,CuOTf.benzene, Cu(OAc)₂, or Cu(I)I, etc., with a chiral ligand).Suitable reaction conditions and exemplary chiral ligands/complexes canbe found in the literature (see, e.g., Detz, et al. Angew. Chem. Int.Ed. 2008, 47, 3777-3780). Contacting compound 6-c with azide 4-b understandard 1,3-dipolar cycloaddition conditions provide compound 6-b. 6-cmay or may not be isolated prior to the addition of compound 4-b. Scheme7 shows an alternate synthesis, leading to compound 7-g via imineformation and subsequent nucleophilic addition, where R^(3a), m, R¹, R²,R³, R⁴, R⁵ and R¹⁵ are as defined herein.

In Scheme 7, amine 2-d is reacted with aldehyde 7-a to afford thecorresponding inline 7-b under standard imine-forming conditions.Compound 7-b is then reacted with Grignaid reagent 7-c to provideFormula I. Alternatively, 2-d can be reacted with aldehyde 7-d to affordimine 7-e, which is then reacted with ethynyl Grignard to providecompound 7-f. Compound 7-f can then be converted to compound 7-g understandard 1,3-dipolar cycloaddition conditions with 4-b as shown inScheme 6. Further, resolution of the isomers of Formula I or compound7-g can be performed using standard chiral separation/resolutionconditions (e.g., chiral chromatography, crystallization, etc.).

Scheme 8 shows another synthesis leading to compound 8-c, where m, R¹,R², R³, R⁴, R⁵ and R¹⁵ are as defined herein.

In Scheme 8, amine 2-d is reacted with appropriately substituted 8-aunder nucleophilic substitution conditions, where Lg is a suitableleaving group, such as a halide (e.g., fluoro, chloro, bromo, iodo) oran activated alcohol (e.g., AcO-, TsO-, TfO-, MsO-, etc.) in thepresence of a base, to provide compound of Formula I. Alternatively,amine 2-d is reacted with ketone 8-b to provide 8-c, which issubsequently reduced to provide compound of 8-c. Resolution of theisomers of Formula I can be performed using standard chiralseparation/resolution conditions (e.g., chiral chromatography,crystallization, etc.).

Scheme 9 shows a synthesis leading to compound 9-e, where m, R¹, R², R³,R⁴, R⁵ and R¹⁵ are as defined herein.

In Scheme 9, amine 6-b is reacted with appropriately substitutedchloroformate 9-a, using a suitable solvent (e.g., DCM, etc.) and base(e.g., proton sponge, etc.) to give compound 9-b. Compound 9-b is thenreacted with a suitable nucleophile 9-c (e.g., acetates, phosphates,etc.) and an iodide salt (e.g., tetrabutylammonium iodide, etc.),followed by a deprotection step if necessary to give compound 9-e. Amine6-b can also be reacted with 1,1′-Carbonyldiimidazole in a suitablesolvent (e.g., DMF, etc.), excess base (e.g., NaH, etc.), and anappropriately substituted alcohol to give compound 9-g.

EXAMPLES

The following examples are included to demonstrate specific embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques to function well in the practice of the disclosure, and thuscan be considered to constitute specific modes for its practice.However, those of skill in the art should, in light of the presentdisclosure, appreciate that many changes can be made in the specificembodiments which are disclosed and still obtain a like or similarresult without departing from the spirit and scope of the disclosure.

List of Abbreviations and Acronyms

Abbreviation Meaning ° C. Degree Celsius Ac Acetyl aq. Aqueous ATPAdenosine triphosphate BOC tert-Butoxycarbonyl br Broad BSA Bovine serumalbumin BLQ Below limit of quantitation Cbz Carboxybenzyl CODCyclooctadiene COPD Chronic obstructive pulmonary disease CpCyclopentadienyl d Doublet DABCO 1,4-Diazabicyclo[2.2.2]octane DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DCE Dichloroethene DCMDichloromethane dd Doublet of doublets DEF N,N-Diethylformamide DMFDimethylformamide DMSO Dimethylsulfoxide dppf1,1′-Bis(diphenylphosphino)ferrocene dt Doublet-triplet DTTDithiothreitol EC₅₀ The half maximal effective concentration EGFREpidermal growth factor receptor eq Equivalents ES/MS Electrospray massspectrometry Et Ethyl FBS Fetal bovine serum g Grams HEPES2-[4-(2-hydroxyethyl)piperazin-1- yl]ethanesulfonic acid HPLC Highpressure liquid chromatography hrs Hours Hz Hertz IBD Inflammatory boweldisease i-pr Isopropyl J Coupling constant (MHz) Kg/kg Kilogram LCMSLiquid chromatography-mass spectrometry LPS Lipopolysaccharide M Molar mmultiplet M+ Mass peak M + H+ Mass peak plus hydrogen Me Methyl mgMilligram MHz Megahertz min Minute ml/mL Milliliter mM Millimolar mmolMillimole MOPS 3-Morpholinopropane-1-sulfonic acid MS Mass spectroscopyMs Mesyl nBu/Bu Butyl nL Nanoliter nm Nanometer NMR Nuclear magneticresonance NP-40 Nonyl phenoxypolyethoxylethanol Ns Nosyl Pd—C/Pd/CPalladium on Carbon pg Pictogram Ph Phenyl PPTS Pyridiniump-toluenesulfonate PS Polystyrene p-TSOH/pTSA p-Toluenesulfonic acid qQuartet q.s. Quantity sufficient to achieve a stated function RBF Roundbottom flask RP Reverse phase RPMI Roswell Park Memorial Institutemedium rt Room temperature s Singlet sat. Saturated t Triplet TBAFTetra-n-butylammonium fluoride TBS tert-Butyldimethylsilyl t-Butert-Butyl TC Thiophene-2-carboxylate TEA Triethanolamine TfTrifluoromethanesulfonyl TFA Trifluoroacetic acid THF TetrahydrofuranTpl-2 Tumor Progression Locus 2 TR-FRET Time-resolved fluorescenceenergy transfer Ts Tosyl δ Chemical shift (ppm) μL/μl Microliter μMMicromolar

Synthesis Cyanoquinoline Core Ethyl(Z)-3-((2-chloro-4-nitrophenyl)amino)-2-cyanoacrylate

A mixture of 2-chloro-4-nitroaniline (1 eq), (Z)-ethyl2-cyano-3-ethoxyacrylate (1.3 eq) and Cs₂CO₃ (1.3 eq) in DMF was heatedat 45° C. overnight. After being cooled to room temperature, the mixturewas poured into water. The formed solid was filtered and washed withwater and dried to give the above-depicted resultant compound as a solidwhich was used for the next step without further purification. ¹H NMR(DMSO-d₆, 300 MHz): δ 11.28 (d, J=12.9 Hz, 1H), 8.84 (d, J=12.9 Hz, 1H),8.42 (d, J=2.4 Hz, 1H), 8.26-8.22 (m, 1H), 8.02 (d, J=9.3 Hz, 1H), 4.27(q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H).

8-Chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile

A suspension of (Z)-ethyl3-((2-chloro-4-nitrophenyl)amino)-2-cyanoacrylate in diphenyl etherunder nitrogen was heated to reflux with a sand bath in a heating mantlefor 24 hours. After cooling to room temperature, the reaction mixturewas poured into hexane and stirred for 2 hours. The mixture was filteredand the filter cake was washed with hexane twice to give titled compoundas a solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 12.86 (br s, 1H), 8.73-8.71 (m,3H).

4,8-Dichloro-6-nitroquinoline-3-carbonitrile

A suspension of8-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile and fivedrops of DMF in POCl₃ was heated at 115° C. overnight. The solution wascooled down to room temperature and the excess of POCl₃ was removed. Theresidue was dissolved in DCM, washed with sat. NaHCO₃, brine and driedover Na₂SO₄. The solution was filtered and concentrated to give a crudeproduct. The residue was triturated with hexane and EtOAc to afford thetitle compound as a solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 9.50 (s, 1H),8.98 (d, J=2.4 Hz, 1H), 8.89 (d, 7=2.4 Hz, 1H).

8-chloro-4-(neopentylamino)-6-nitroquinoline-3-carbonitrile

4,8-dichloro-6-nitroquinoline-3-carbonitrile (615 mg, 2.29 mmol),neopentylamine (220 mg, 0.25 mmol) and triethylamine (278 mg, 2.75 mmol)in iso-propanol (4 mL) were heated under microwave conditions at 150° C.for 45 minutes. The reaction was cooled to room temperature. Water wasadded and the resulting precipitate was collected via filtration. Thecrude product was used in the next step without further purification.ES/MS 319.1 (M+H⁺).

Alternatively, 4,8-dichloro-6-nitroquinoline-3-carbonitrile (3000 mg,11.2 mmol), neopentylamine (1073 mg, 12.3 mmol) and triethylamine (1246mg, 12.3 mmol) in iso-propanol (60 mL) were heated at 80° C. for 4 hrs.The reaction was cooled to room temperature. Removed the solvents andpurified the crude reaction product via chromatography on silica gel(eluent: EtOAc/hexanes) yielding the product. ES/MS (M+H⁺) 319.1.

Synthesis of(S)-8-chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

6-amino-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile

8-chloro-4-(neopentylamino)-6-nitroquinoline-3-carbonitrile (699 mg, 2.2mmol), calcium chloride (483.6 mg, 3.28 mmol), and iron powder (612.3mg, 10.96 mmol) were heated in ethanol (22 mL)/water (2.2 mL) at 60° C.for 1 hour. The reaction was cooled to room temperature and solids wereremoved via filtration. The solids were washed with EtOAc and thecombined organic layers were washed with aqueous sodium bicarbonatesolution, brine, and were dried over sodium sulfate. Filtration andevaporation of all volatiles yielded the product. ES/MS 289.1 (M+H⁺).

Alternatively,8-chloro-4-(neopentylamino)-6-nitroquinoline-3-carbonitrile (2,000 mg,6.2 mmol) and tin chloride (7079 mg, 31.3 mmol) were heated at 70° C.for 4 hours. Additional tin chloride (2832 mg, 12.6 mmol) was added.After 5 hrs, the reaction was reaction was cooled to room temperature.Half of the ethanol was removed under reduced pressure. The mixture wasadded to NaHCO₃ (200 mL) and diluted with EtOAc (500 mL). The organicphase was washed with brine (200 mL) and dried over sodium sulfate. Thesolvent was removed under reduced pressure, providing the desiredmaterial. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.32 (d, J=2.1 Hz,1H), 7.29 (t, J=7.3 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 5.74 (s, 2H), 3.66(d, J=6.6 Hz, 2H), 0.96 (s, 9H).

(R)-8-chloro-6-((1-(6-fluoro-2-methylpyridin-3-yl)prop-2-yn-1-yl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

A mixture of acetonitrile (800 ml) and methanol (800 ml), degassed withargon, was added to Cu(I)iodide (3.3 g, 17.3 mmol) and bis-oxazolineligand (10.8 g, 20.7 mmol) and the mixture was stirred under inertatmosphere for 90 minutes at ambient temperature. The mixture was cooledto 5° C. To a 5 L rector was added6-amino-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile (100 g, 346mmol), l-(6-fluoro-2-methylpyridin-3-yl)prop-2-yn-1-yl acetate (86 g,415 mmol), and sodium acetate (35.6 g, 434 mmol). The reactor wascharged with a mixture of acetonitrile (800 ml) and methanol (800 ml)and degassed with argon. The reactor was cooled to −5° C. and chargedwith the solution containing Cu(I)iodide and bis-oxazoline ligand over20 minutes via cannulation. After stirring at −5° C. for 48 hours, themixture was warmed to 5° C. and to the mixture was added 4M NH₄Cl (2 L)over 1 hour. The mixture was warmed to 20° C. and the resulting solidswere filtered and washed with water (500 mL). The wet cake wastransferred to a reactor and heated with a 1:1 mixture of isopropylacetate and ethyl acetate (3 L) and heated to 40° C. The solids werefiltered through celite, the aqueous layer was removed from thefiltrate, and the organic layer was concentrated under vacuum. Theresulting solid was suspended in dichloromethane (1.5 L) and heated toreflux and hexane (750 mL) was slowly added. The resulting suspensionwas warmed to 5° C. over 4 hours. The precipitated solids were filtered(95 g) and recrystallized from dichloromethane and hexanes to give thetitle compound. 1H NMR (400 MHz, Methanol-d4) δ 8.27 (s, 1H), 8.24 (t,J=8.1 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.97 (dd,J=8.4, 2.8 Hz, 1H), 5.76 (d, J=2.2 Hz, 1H), 3.94 (d, J=13.9 Hz, 1H),3.71 (d, J=13.9 Hz, 1H), 3.06 (d, J=2.3 Hz, 1H), 2.60 (s, 3H), 1.02 (s,9H). ES/MS 436.34 (M+H⁺).

(S)-8-chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

A 500 ml round bottom flask was charged with1-(difluoromethyl)cyclopropanamine hydrochloride (8.2 g, 57.4 mmol). Theround bottom flask was placed in a water bath and charged withacetonitrile (34 mL) followed by N,N-diisopropylethylamine (10.3 ml,59.6 mmol). The mixture was stirred until homogeneous and to the mixturewas added a solution of 2-azido-1,3-dimethylimidazoliniumhexafluorophosphate (16.4 g, 57.4 mmol) in acetonitrile (32 ml) over 10min. The mixture was stirred at 30° C. for 8 hours andN,N-diisopropylethylamine (1.98 ml, 11.47 mmol) was added and stirred at30° C. for 18 hours. A jacketed 500 ml flask was charged with(R)-8-chloro-6-((1-(6-fluoro-2-methylpyridin-3-yl)prop-2-yn-1-yl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(20 g, 45.9 mmol) and kept at 20° C. using a circulating chiller. Theflask was charged with tetrahydrofuran (40 mL), copper(II) sulfatepentahydrate (1.2 g, 4.6 mmol), sodium ascorbate (2.7 g, 13.8 mmol), andwater (16 mL). To the mixture was added the azide solution from aboveover 10 min in quarter portions. The mixture was stirred at 22° C. for18 hours. The reaction was quenched with tributylphosphine (3.4 ml, 13.8mmol). After stirring for 20 minutes, the mixture was diluted with ethylacetate (160 mL) and washed with 0.5M aqueous HCl (160 mL). The organiclayer was stirred with 0.5M ammonium hydroxide (160 mL) for 3 hours. Theorganic layer was dried with Na₂SO₄, filtered, and concentrated. Thecrude product was diluted with ethyl acetate (15 mL) and the mixture washeated to 50° C. To the mixture was added methyl tert-butyl ether (150mL). The solution was cooled to 20° C. and stirred for 18 hours. Thesolids were filtered, washed with (10:1 MTBE:EtOAc) and dried undervacuum. The filtrate was concentrated, purified by silicachromatography, and the purified product was precipitated from ethylacetate and methyl tert-butyl ether. The products were combined to givethe titled compound.

(S)-6-6(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrile

A mixture of(S)-8-chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(95 mg, 0.14 mmol), zinc powder (1.2 mg, 0.02 mmol), Zn(CN)₂, andPd(dppf)C₁₋₂ in N,N-dimethylacetamide was degassed with argon for 2 min.The mixture was heated in a microwave reactor at 200° C. for 15 minutes.The mixture was diluted with ethyl acetate (10 mL) and washed withsaturated NaHCO₃ (aq, 5 mL), and brine (5 mL). The organic phase wasdried over sodium sulfate and treated with thiol functionalized silicato remove residual palladium. The solvent was removed under reducedpressure. The residue was subjected to flash chromatography using ethylacetate and hexanes. The fractions containing product were combined andthe solvent was removed under reduced pressure. The residue was taken upin methanol (1 mL) and water (1 mL) with 2 drops of TFA and purified bypreparative HPLC using acetonitrile and water with 0.5% trifluoroaceticacid to give the title compound as the trifluoroacetic acid salt. 1H NMR(400 MHz, Methanol-d4) δ 8.36 (s, 1H), 8.05 (d, J=1.3 Hz, 1H), 7.84-7.75(m, 2H), 7.11 (t, J=2.1 Hz, 1H), 6.86 (dd, J=8.5, 2.7 Hz, 1H), 6.24 (s,1H), 5.94 (t, J=54.7 Hz, 1H), 3.89 (d, J=13.8 Hz, 1H), 3.70 (dd, J=13.8,1.6 Hz, 1H), 2.50 (s, 3H), 1.55-1.50 (m, 4H), 0.89 (s, 9H). ES/MS 560.24(M+H+).

Example 1 (Phosphonooxy)methyl(S)-((l-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate

Synthesis of chloromethyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate

To a DCE (1 mL) solution of(S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrilehydrochloride salt (100 mg, 0.159 mmol) was added DIPEA (616 mg, 4.77mmol) followed by chloromethyl carbonochloridate (1024 mg, 7.94 mmol) atroom temperature. After heating at 50° C. overnight, the reaction wascooled to room temperature and extracted with ethyl acetate (100 mL).The extraction was washed with brine, dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified bysilica gel chromatography to afford 85 mg of the desired product MS(m/z): 685.261 [M+H]⁺.

Synthesis of ((di-tert-butoxyphosphoryl)oxy)methyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate

To a DMF (5 mL) solution of chloromethyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate(85 mg, 0.124 mmol) was added potassium di-tert-butyl phosphate (77 mg,0.37 mmol) and tetrabutylammonium Iodide (22.9 mg, 0.06 mmol) at roomtemperature. After heating to 70° C. for 4 hrs, the reaction was cooledto room temperature and extracted with ethyl acetate (100 mL), theextraction was washed with brine, dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified by silica gelchromatography to afford 93 mg of the desired product MS (m/z): 858.956[M+H]⁺.

Synthesis of (phosphonooxy)methyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate

To an ACN:water (4 mL, 1:1) solution of((di-tert-butoxyphosphoryl)oxy)methyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate(93 mg, 0.108 mmol), was added AcOH (2 mL). After heating to 55° C. for4 hrs, the reaction was concentrated under vacuum. The resulting residuewas purified by RP-HPLC to yield 10 mg of (phosphonooxy)methyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamatetrifluoroacetic acid salt MS (m/z): 858.956 [M+H]⁺.

Example 2((((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methylL-alaninate

Synthesis of((((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methyl(tert-butoxycarbonyl)-L-alaninate

To a DMF (1 mL) solution of chloromethyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate(73 mg, 0.43 mmol) was added potassium bicarbonate (37 mg, 0.43 mmol),potassium iodide (22.9 mg, 0.06 mmol), and BOC-L-alanine (55 mg, 0.29mmol) and stirred at room temperature for 16 h. The reaction was pouredonto a brine solution (˜50 mL), extracted with ethyl acetate (30 mL),dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was purified by silica gel chromatography to afford 100 mg ofthe desired product MS (m/z): 839.0 [M+H]+.

Synthesis of((((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methylL-alaninate

A DCM:TFA (4 mL, 1:1) solution of((((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methyl(tert-butoxycarbonyl)-L-alaninate (100 mg, 0.12 mmol), was stirred at rtfor 2 h. The reaction was concentrated under vacuum and purified byRP-HPLC to yield 80 mg of the titled compound as a trifluoroacetic acidsalt MS (m/z): 739.2 [M+H]⁺.

Example 3((((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methylL-valinate

The titled compound was made similar to Example 2 using BOC-L-valine inplace of BOC-L-alanine. MS (m/z): 767.1 [M+H]⁺

Example 4 3-(Phosphonooxy)propyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate

Synthesis of 3-chloropropyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate

To a DCM (3 mL) solution of(S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile(630 mg, 1.1 mmol) was added proton sponge (683 mg, 3.2 mmol) followedby 3-chloropropyl carbonochloridate (417 mg, 2.6 mmol) at roomtemperature. After stirring at rt for 24 h, the reaction wasconcentrated under vacuum and residue was purified by silica gelchromatography to afford 233 mg of the desired product MS (m/z): 714.3[M+H]+.

Synthesis of 3-((di-tert-butoxyphosphoryl)oxy)propyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate

To a THF (2 mL) solution of 3-chloropropyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate(100 mg, 0.14 mmol) was added potassium di-tert-butyl phosphate (52 mg,0.2 mmol) and tetrabutylammonium iodide (21 mg, 0.06 mmol) at roomtemperature. After heating to 50° C. for 16 hrs, the reaction was cooledto room temperature and extracted with ethyl acetate (100 mL), theextraction was washed with brine, dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified by silica gelchromatography to afford 25 mg of the desired product MS. (m/z): 887.9[M+H]⁺.

Synthesis of 3-(Phosphonooxy)propyl(S)-(0-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate

A DCM:TFA (4 mL, 1:1) solution of3-((di-tert-butoxyphosphoryl)oxy)propyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate(25 mg, 0.28 mmol) was stirred for 2 h at rt. The reaction wasconcentrated under vacuum and the resulting residue was purified byRP-HPLC to yield 15 mg of the title compound as a trifluoroacetic acidsalt. MS (m/z): 776.1 [M+H]+.

Example 5 3-Hydroxypropyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate

To a suspension of(S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrilein DMF (0.5 mL) was added NaH (60% in mineral oil) (60%, 12.14 mg, 0.3mmol). After stirring for 10 mins, di(imidazol-1-yl)methanone (24.6 mg,0.15 mmol) was added and the mixture was stirred at RT for 1 h. To themixture was added 1,3-propanediol (0.25 mL) and the reaction was stirredfor 1 h. The mixture was acidified with 5% TFA in water and the productwas purified via RP-HPLC (eluent: water/MeCN 0.1% TFA) to yield theproduct as trifluoroacetate salt. ES/MS: 695.3 (M+H±).

Example 6 (Phosphonooxy)methyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(neopentylamino)quinolin-6-yl)carbamate

The titled compound was made similar to Example 1 using(S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrilein place of(S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrilehydrochloride salt. MS (m/z): 689.968 [M+H]⁺.

Example 7(S)-((((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methylacetate

To a suspension of chloromethyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(neopentylamino)quinolin-6-yl)carbamate(63 mg, 0.1 mmol) in DMF (3 mL) was added tetrabutylammonium iodide (18mg, 0.05 mmol) followed by acetoxypotassium (20 mg, 0.2 mmol). Afterheating to 60° C. for 2 hrs, the reaction was cooled to room temperatureand extracted with ethyl acetate (30 mL), the extraction was washed withbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. The mixture was acidified with 5% TFA in water and the productwas purified via RP-HPLC (eluent: water/MeCN 0.1% TFA) to yield theproduct as trifluoroacetate salt. MS (m/z): 652.1 [M+H]⁺

Example 8(S)-((((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(neopentylamino)quinolin-6-yl)carbamoyl)oxy)methyl1-methylpiperidine-4-carboxylate

To a suspension of 1-methylpiperidine-4-carboxylic acid (13.68 mg, 0.096mmol) in DMF (3 mL) was added KHMDS (1M solution in THF, 0.08 mL), after15 min chloromethyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(neopentylamino)quinolin-6-yl)carbamate(20 mg, 0.032 mmol) was added followed by tetrabutylammonium iodide(5.88 mg, 0.016 mmol). After 2 hrs heating at 60° C., the reaction wasextracted with ethyl acetate, washed with brine and concentrated undervacuum. The resulting residue was purified by prep-HPLC to yield 13.2 mgof the title compound as the trifluoroacetic acid salt MS. (m/z): 735.29[M+H]⁺

Example 9 (R)-1-methoxypropan-2-yl((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(neopentylamino)quinolin-6-yl)carbamate

To a solution of(S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrile(69 mg, 0.12 mmol) in pyridine (1 mL) was added (R)-1-methoxypropan-2-ylcarbonochloridate (200 mg, 1 mmol) at 0° C. The reaction was warmed tort and heated to 50° C. for 16 h. Upon cooling the reaction to roomtemperature the reaction was extracted with ethyl acetate (100 mL),washed with brine, dried over anhydrous sodium sulfate and concentratedunder vacuum. The resulting residue was purified by prep-HPLC to yield84 mg of the title compound as the trifluoroacetic acid salt. MS (m/z):652.16 [M-t-Bu]⁺

Example 10 (Phosphonooxy)methyl((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-4(R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)carbamate

The titled compound was made similar to Example 1 using6-(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinoline-3,8-dicarbonitrilein place of(S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrilehydrochloride salt. MS (m/z): 704.028 [M+H]⁺.

Example 11(48)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino)methyldihydrogen phosphate

Synthesis of(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino)methyldi-tert-butyl phosphate

To a solution of6-(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinoline-3,8-dicarbonitrile(60 mg, 0.109 mmol) in DCE (2 mL) was added DIPEA (141.8 mg, 1.09 mmol)and di-tert-butyl (chloromethyl) phosphate (112.96 g, 0.437 mmol) atroom temperature. After heated to 50° C. for overnight, the reaction wascooled to room temperature and extracted with ethyl acetate (100 mL),the extraction was washed with brine, dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column for purification, afford 22 mg of(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino)methyldi-tert-butyl phosphate. MS (m/z): 715.68 [M-t-Bu]±.

Synthesis of(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino)methyldihydrogen phosphate

A solution of(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino)methyldi-tert-butyl phosphate (22 mg, 0.1 mmol) in a mixture of ACN (2 mL) andwater (2 mL), was added AcOH (2 mL) was heated to 70° C. for 4 hrs. Thereaction was cooled, concentrated under vacuum, and the resultingresidue was purified by prep-HPLC to yield 28.5 mg of(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino)methyldihydrogen phosphate trifluoroacetic acid salt MS (m/z): 659.935 [M+H]±.

Example 12 (R)-1-methoxypropan-2-yl((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)carbamate

To a solution of6-(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinoline-3,8-dicarbonitrile(25 mg, 0.045 mmol) in DCE (1 mL) was added DIPEA (117.6 mg, 0.9 mmol)and (R)-1-methoxypropan-2-yl carbonochloridate (69.4 mg, 0.46 mmol) atroom temperature. After heating to 50° C. for 16 h, the reaction wascooled to room temperature, extracted with ethyl acetate (100 mL),washed with brine, dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by RP-HPLC to afford 7.2 mg ofthe titled compound. MS (m/z): 666.17 [M-t-Bu]⁺

Example 132-(48)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)(3,8-dicyano-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinolin-6-yl)amino)-2-oxoaceticacid

To a solution of6-(((S)-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(((R)-3,3-dimethylbutan-2-yl)amino)quinoline-3,8-dicarbonitrile(50 mg, 0.095 mmol) in THF (5 mL) was added DMAP (56 mg, 0.45 mmol)followed by oxalyl dichloride (23 mg, 0.18 mmol) at room temperature.After heating to 50° C. for 4 hrs, the reaction was cooled to roomtemperature and extracted with ethyl acetate (100 mL), washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by RP-HPLC to afford 27 mg of the titlecompound. MS (m/z): 621.9 [M-t-Bu]⁺.

Example 14 3-hydroxypropyl(S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate

To a solution of(S)-8-chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(150 mg, 0.26 mmol) and di(imidazol-1-yl)methanone (106.86 mg, 0.66mmol) in DMF (1.0 mL) was added NaH (15.82 mg, 0.66 mmol) in 4 portions.After stirring for 30 minutes, 1,3-propanediol (0.5 mL) was added andthe mixture was stirred at ambient temperature for 2 h. The mixture wasextracted with EtOAc (3 mL) and washed 3 times with 5% LiCl (aq, 3 mL).The organic layer was dried with Na₂SO₄, filtered, and concentrated. Thecrude product was taken to next step without further purification.ES/MS: 671.20 (M+H±).

Example 15 3-(Phosphonooxy)propyl(S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate

To 3-hydroxypropyl(S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate(0.11 g, 0.17 mmol) was added acetonitrile (2 mL) and EtN(i-Pr)₂ (145.48μl, 0.84 mmol). To the stirring mixture was added phosphorus(V)oxychloride (47.13 μl, 0.5 mmol) and the mixture was stirred for 30minutes. To the reaction was added 1M HCl (0.5 mL). After stirring for 1min, the mixture was partially concentrated, diluted with DMF, andpurified via RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the productas a trifluoro acetate salt (30 mg). ES/MS: 751.20 (M+H±).

Example 16 2-Hydroxyethyl(S)-41-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate

To a suspension of(S)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile(100 mg, 0.17 mmol) in DMF (0.5 mL) was added NaH (12.14 mg, 0.51 mmol).After stirring for 1 minute, di(imidazol-1-yl)methanone (41.01 mg, 0.25mmol) in DMF (0.2 mL) was added dropwise and the mixture was stirred atambient temperature for 1 h. Additional CDI (1 eq) and NaH (1 eq) wasadded and the reaction was stirred for 30 minutes. To the mixture wasadded ethylene glycol (0.2 mL) and the reaction was stirred for 1 h. Themixture was diluted with EtOAc (20 mL) and washed 3 times with 5% LiCl(aq, 15 mL). The organic layer was dried with Na₂SO₄, filtered, andconcentrated. ES/MS: 681.22 (M+H⁺).

Example 17 2-(Phosphonooxy)ethyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate

To 2-hydroxyethyl(S)-((1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)carbamate(0.11 g, 0.17 mmol) was added acetonitrile (2 mL) and EtN(i-Pr)₂ (145.48μl, 0.84 mmol). To the stirring mixture was added phosphorus(V)oxychloride (47.13 μl, 0.5 mmol) and the mixture was stirred for 30minutes. To the reaction was added 1M HCl (0.5 mL). After stirring for 1minute, the mixture was partially concentrated, diluted with DMF, andpurified via RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the productas a trifluoro acetate salt (40 mg). ES/MS: 723.20 (M+H±).

Example 18 Chloromethyl(S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate

A solution of(S)-8-chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile(0.3 g, 0.53 mmol), chloromethyl carbonochloridate (0.09 mL, 1.05 mmol),and proton sponge (0.25 g, 1.16 mmol) in dichloromethane (3 mL) wasstirred for 15 hours at ambient temperature. The product was purified bysilica chromatography using EtOAc in hexane (0-100%). ES/MS: 661.20(M+H⁺).

Example 19 ((Di-tert-butoxyphosphoryl)oxy)methyl(S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate

A suspension of chloromethyl(S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate(30.03 mg, 0.12 mmol), and tetrabutylammonium iodide (1 mg) in MeTHF(0.5 mL) was stirred at 60° C. for 1 hour. The mixture was diluted withEtOAc (3 mL) and extracted twice with water (3 mL) followed by 0.1M NaCl(aq, 10 mL). The organic layer was dried with Na₂SO₄, filtered, andconcentrated. ES/MS: 661.20 (M+H±).

Example 20 (Phosphonooxy)methyl(S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate

A solution of ((di-tert-butoxyphosphoryl)oxy)methyl(S)-(8-chloro-3-cyano-4-(neopentylamino)quinolin-6-yl)((1-(1-(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)carbamate(50 mg, 0.06 mmol) in dichloromethane (0.1 mL) and trifluoroacetic acid(0.1 mL) was stirred at 20° C. for 1 hour. The mixture was concentratedand purified via RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield theproduct as a trifluoro acetate salt. ES/MS: 761.20 (M+H±).

COMPOUND EXAMPLES

The following compounds were prepared according to the Examples andProcedures described herein (and indicated in Table 1 underExample/Procedure) using the appropriate starting material(s) andappropriate protecting group chemistry as needed.

TABLE 1 Example ¹H NMR  1

¹H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.21 (s, 1H), 8.05 (s,1H), 7.71 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H),7.39 (s, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 5.78(s, 1H), 5.47 (s, 1H), 3.56 (s, 5H), 2.75 (s, 1H), 2.43 (s, 6H),1.19-0.82 (m, 9H).  2

¹H NMR (400 MHz, Methanol-d₄) δ 8.53 (s, 1H), 8.24 (dd, J = 8.1, 1.2 Hz,1H), 8.08-7.75 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 7.47 (s, 1H), 7.36(dd, J = 7.5, 1.3 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.6Hz, 1H), 6.04 (d, J = 5.9 Hz, 1H), 5.79 (s, 1H), 4.16 (q, J = 7.2 Hz,1H), 3.95 (d, J = 13.8 Hz, 1H), 3.64 (s, 3H), 2.74 (s, 1H), 2.42 (s,6H), 1.51 (d, J = 7.2 Hz, 3H), 0.99 (s, 7H).  3

¹H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.24 (dd, J = 8.2, 1.1 Hz,1H), 8.06 (s, 1H), 7.96 (s, 1H), 7.79 (s, 1H), 7.57 (d, J = 7.7 Hz, 1H),7.47 (s, 1H), 7.41-7.34 (m, 1H), 7.25 (t, J = 7.8 Hz, 1H), 6.94 (d, J =7.6 Hz, 1H), 6.12 (d, J = 5.8 Hz, 1H), 5.74 (s, 1H), 4.03-3.88 (m, 2H),3.72 (d, J = 13.8 Hz, 1H), 3.65 (s, 3H), 2.74 (s, 1H), 2.43 (s, 6H),2.31-2.18 (m, 1H), 2.06 (s, 1H), 0.99 (d, J = 16.3 Hz, 16H).  4

¹H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 1H), 8.21 (dd, J = 8.2, 1.1 Hz,1H), 8.16-8.11 (m, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 7.58 (d, J = 7.7 Hz,1H), 7.47 (s, 1H), 7.38 (dd, J = 7.5, 1.3 Hz, 1H), 7.23 (t, J = 7.8 Hz,1H), 6.99 (d, J = 7.6 Hz, 1H), 4.31 (qt, J = 11.1, 5.9 Hz, 2H), 4.04 (d,J = 13.9 Hz, 1H), 3.87 (q, J = 6.3 Hz, 2H), 3.78 (d, J = 13.9 Hz, 1H),3.64 (s, 3H), 2.73 (s, 1H), 2.44 (s, 6H), 1.90 (t, J = 6.1 Hz, 2H), 1.01(s, 9H).  5

¹H NMR (400 MHz, CD₃OD) δ 8.62 (s, 1H), 8.22 (dd, J = 8.1, 1.1 Hz, 1H),8.12 (d, J = 2.0 Hz, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.58 (d, J = 7.7Hz, 1H), 7.50-7.38 (m, 2H), 7.25 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 7.6Hz, 1H), 4.29 (t, J = 6.2 Hz, 2H), 4.01 (d, J = 13.9 Hz, 1H), 3.81 (d, J= 13.9 Hz, 1H), 3.64 (s, 3H), 3.48-3.40 (m, 1H), 2.74 (s, 1H), 2.43 (s,6H), 1.76 (p, J = 6.2 Hz, 2H), 1.04 (s, 9H).  6

H NMR (400 MHz, Chloroform-d) δ 8.71 (s, 1H), 8.59 (s, 1H), 8.14 (s,1H), 7.68 (d, J = 17.5 Hz, 2H), 7.05 (s, 1H), 6.54 (d, J = 6.8 Hz, 1H),5.44 (d, J = 16.4 Hz, 1H), 5.29 (s, 1H), 3.90 (s, 2H), 2.71 (s, 1H),2.54 (s, 3H), 2.37 (s, 6H), 1.06 (s, 9H).  7

¹H NMR (400 MHz, Chloroform-d) δ 8.82 (s, 1H), 8.65 (s, 1H), 7.72-7.53(m, 2H), 7.01 (s, 1H), 6.45 (d, J = 8.5 Hz, 1H), 6.00-5.76 (m, 2H),5.73-5.56 (m, 1H), 3.91-3.65 (m, 2H), 2.70 (d, J = 48.6 Hz, 4H), 2.41(s, 5H), 2.09 (s, 3H), 1.21 (d, J = 27.5 Hz, 9H).  8

¹H NMR (400 MHz, Chloroform-d) δ 8.66 (d, J = 7.1 Hz, 1H), 7.61 (d, J =34.7 Hz, 2H), 7.47 (s, 1H), 7.04 (d, J = 14.4 Hz, 1H), 6.49-6.45 (m,1H), 6.01 (s, 1H), 5.92 (d, J = 5.5 Hz, 1H), 5.75 (s, 1H), 3.86-3.61 (m,4H), 3.46 (s, 1H), 2.80 (d, J = 6.3 Hz, 3H), 2.69-2.63 (m, 3H), 2.55 (s,1H), 2.40 (t, J = 1.4 Hz, 6H), 2.32 (s, 1H), 2.17 (s, 3H), 1.16 (d, J =1.7 Hz, 9H).  9

1H NMR (400 MHz, Chloroform-d) δ 8.66 (s, 2H), 7.77-7.66 (m, 2H), 7.59(s, 1H), 6.98 (s, 1H), 6.55 (dd, J = 8.5, 3.2 Hz, 1H), 5.97 (s, 1H),5.12-5.02 (m, 1H), 3.83 (d, J = 4.7 Hz, 1H), 3.73 (d, J = 3.8 Hz, 1H),3.42-3.30 (m, 2H), 3.27 (s, 3H), 2.75 (s, 1H), 2.58 (s, 3H), 2.40 (d, J= 0.8 Hz, 6H), 1.25-1.10 (m, 12H). 12

¹H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 8.51 (d, J = 2.2 Hz, 1H),7.80-7.70 (m, 2H), 7.55 (s, 1H), 6.97 (s, 1H), 6.59 (dd, J = 8.6, 3.0Hz, 1H), 5.95 (d, J = 10.0 Hz, 1H), 5.07 (d, J = 3.4 Hz, 1H), 4.64 (t, J= 8.2 Hz, 1H), 3.33 (dd, J = 10.6, 3.2 Hz, 1H), 3.27 (s, 3H), 2.75 (s,1H), 2.57 (s, 3H), 2.39 (s, 6H), 1.39 (d, J = 6.3 Hz, 3H), 1.19 (d, J =6.4 Hz, 3H), 1.09 (s, 9H). 13

¹H NMR (400 MHz, Chloroform-d) δ 8.66 (d, J = 6.5 Hz, 1H), 7.69 (d, J =8.1 Hz, 1H), 7.66 (d, J = 4.5 Hz, 1H), 7.32 (d, J = 11.0 Hz, 1H), 6.88(d, J = 36.1 Hz, 1H), 6.50 (t, J = 10.2 Hz, 1H), 4.74 (s, 1H), 2.75 (d,J = 3.2 Hz, 1H), 2.62 (s, 3H), 2.40 (d, J = 6.4 Hz, 6H), 1.38 (d, J =6.8 Hz, 3H), 1.04 (d, J = 33.2 Hz, 9H). 14

¹H NMR (400 MHz, Methanol-d4) S 8.62 (s, 1H), 8.22 (dd, J = 8.1, 1.1 Hz,1H), 8.12 (d, J = 2.0 Hz, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.58 (d, J =7.7. Hz, 1H), 7.50-7.38 (m, 2H), 7.25 (t, J = 7.8 Hz, 1H), 6.97 (d, J =7.6 Hz, 1H), 4.29 (t, J = 6.2 Hz, 2H), 4.01 (d, J = 13.9 Hz, 1H), 3.81(d, J = 13.9 Hz, 1H), 3.64 (s, 3H), 3.48- 3.40 (m, 1H), 2.74 (s, 1H),2.43 (s, 6H), 1.76 (p, J = 6.2 Hz, 2H), 1.04 (s, 9H). 15

¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.26-7.96 (m, 3H), 7.69 (t, J =8.1 Hz, 1H), 7.12 (s, 1H), 6.71 (dd, J = 8.6, 2.9 Hz, 1H), 5.93 (t, J =54.6 Hz, 1H), 4.38-4.19 (m, 2H), 4.13 (d, J = 14.0 Hz, 1H), 3.94-3.77(m, 3H), 2.65 (s, 3H), 1.97-1.77 (m, 2H), 1.65-1.46 (m, 4H), 1.10 (s,9H). 17

¹H NMR (400 MHz, CD₃OD) δ 8.62 (s, 1H), 8.44 (s, 1H), 8.20 (s, 1H), 8.03(d, J = 2.0 Hz, 1H), 7.75 (t, J = 8.1 Hz, 1H), 7.15 (s, 1H), 6.74 (dd, J= 8.6, 2.9 Hz, 1H), 5.96 (t, J = 54.7 Hz, 2H), 5.61 (dd, J = 16.5, 5.5Hz, 1H), 5.49 (dd, J = 13.8, 5.4 Hz, 1H), 4.14 (d, J = 13.9 Hz, 1H),3.87 (d, J = 14.0 Hz, 1H), 2.61 (s, 3H), 1.63- 1.45 (m, 4H), 1.11 (s,9H). 20

¹H NMR (400 MHz, CD₃OD) δ 8.62 (s, 1H), 8.30-8.12 (m, 3H), 8.09 (s, 1H),7.60 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.40 (dd, J = 7.7, 1.3 Hz, 1H),7.23 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 4.63-4.46 (m, 1H),4.35-4.01 (m, 4H), 3.76 (d, J = 13.9 Hz, 1H), 3.63 (s, 3H), 2.75 (s,1H), 2.46 (s, 6H), 1.03 (s, 9H).

Biological Assays Example 21 Human and Dog GI S9 Stability

GIS9 stability assays were performed. Generally, a substrateconcentration of 2 μM was used, a protein concentration of 1.0 mg/mLintestinal S9 was used, and a reaction buffer of 1× phosphate bufferedsaline (PBS) was used. Intestinal S9 was provided by BioIVT (dog) orXenotech (human). Reaction compositions contained 5 μL of compound ofinterest (prepared as 100 μM stock solution, 1:1 ACN:H₂O) and 245 μL ofintestinal S9 solution (S9 was diluted with 1×PBS to a proteinconcentration of 1.02 mg/ML) and were provided as 250 μL total volumeper well. At time points of 0 min, 10 min, 20 min, 30 min, 60 min, and120 min, 25 μL at each timepoint was added to a plate with 225 μLquenching solution (10% MeOH, 90% ACN, and 200 nM Labetalol as internalstandard). Plates were vortexed, and then centrifuged at 3000×G for 30minutes. 150 μL of supernatant was transferred to new plates and 150 μLwater was added. New plates were vortexed to mix.

Samples were analyzed with a Leap HTC Autosampler and a Dionex UltiMate3000 HPLC system interfaced to a Thermo Q-Exactive mass spectrometeroperation in positive ion electrospray mode. A Thermo ScientificHypersil GOLD (1.9 μM particle size, 50×2.1 mm) HPLC column was used andmobile phase was pumped at 0.5 mL/min. Elution of analytes was achievedby a series of linear gradients of acetonitrile in water containing 0.1%(v/v) formic acid. Quantification was by analyte/internal standard peakarea ratio (PAR). Results are shown in Table 2 below.

TABLE 2 Human Dog Example GI S9 T½ (min) GI S9 T½ (min)  1 43 26  2 <1 1 4 21 12  6 25 14  7 3  8 165  9 789 10 26 20 11 ND ND 12 477 528 13 789789

Example 22 Solubility in FaSSIF and FeSSIF

The aqueous solubility of compounds over a time of 2.5 hours wasassessed. Solubility was determined at ambient temperature in bufferedfasted-state simulated intestinal fluid (FaSSIF, pH 6.5) and bufferedfed-state simulated intestinal fluid (FeSSIF, pH 5.0) prepared in-houseusing BioRelevant Simulated Intestinal Fluid (SIF) powder. Solids wereadded to FaSSIF or FeSSIF in 1.5-mL Eppendorf tubes, sonicated for 1minute, then agitated for 2.5 hours in an Eppendorf ThermoMixer C. Todetermine concentration in solution, the suspensions were centrifugedfor 10 min at 14,800 rpm and supernatants were diluted to a volume of 1mL with 1:1 v/v acetonitrile:water. All diluted supernatants wereanalyzed by UPLC using a Waters Acquity UPLC with a PDA UV detector.Results are depicted in Table 3.

TABLE 3 FaSSIF (pH 6.5) FeSSIF (pH 5.0) Example (μg/mL) (μg/mL)1 >1580 >2170 2 >1881 >1908 4 4 210 7 12 42 8 77 450 9 12 52

Example 23

Human and Dog Plasma Stability

Plasma stability assays were performed in human and dog. Duplicate setswere performed with a tecan liquid handler or with cluster tubes in aheat block. Generally, a substrate concentration of 2 μM was used.Plasma in sodium EDTA was provided by BioIVT as whole plasma with K2 EDAas anti-coagulent. Reaction compositions were prepared by combining 6 μLcompound (compound (100 μM stock solution, 1:1 ACN:H2O) with 294 μLplasma in an incubation well of a plate. Samples were assessed at timepoints of 3 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, and 4 hours.At each time point, 25 μL was added to a plate with 225 μL quenchingsolution (100% ACN with 200 nM propranolol as internal standard). Afterthe plates were vortexed, they were centrifuged at 3000 rpm for 30minutes. 150 μL of supernatant was transferred to a new plate and 150 μLwater was added. New plates were vortexed to mix.

Samples were analyzed with a Leap HTC Autosampler and a Dionex UltiMate3000 HPLC system interfaced to a Thermo Q-Exactive mass spectrometeroperation in positive ion electrospray mode. A Thermo ScientificHypersil GOLD (1.9 μM particle size, 50×2.1 mm) HPLC column was used andmobile phase was pumped at 0.5 mL/min. Elution of analytes was achievedby a series of linear gradients of acetonitrile in water containing 0.1%(v/v) formic acid. Quantification was by analyte/internal standard peakarea ratio (PAR). Results are shown in Table 4 below.

TABLE 4 Human Dog Example Plasma T½ (min) Plasma T½ (min) 1 369 278 2 143 8 237 9 1584

Example 24

In Vivo Dog Pharmacokinetics Experiments

In vivo dog pharmacokinetic experiments of compound B and C wereassessed as follows.

Compound B was dosed as a powder in capsule to beagle dogs (N=3) usingthe following formulation: 57.5% by weight of amorphous compound B (9.7mg-eq/kg), 4.7% crospovidone; 18.7% Lactose, monohydrate; 0.4% Magnesiumstearate; 18.7% microcrystalline cellulose. Compound A was dosedseparately as a powder in capsule to beagle dogs (N=3) using thefollowing formulation: 20% of amorphous compound A, 0.75% magnesiumstearate, 3% hydroxypropylcellulose, 5% tocopheryl polyethylene glycolsuccinate, 20% hydroxypropyl methylcellulose, and 51.25%microcrystalline cellulose. Samples were assessed for the presence ofCompound B, proposed Intermediate A, and Compound A. FIG. 1 shows plasmaconcentrations of Compound A (nM) during a 72 hour time period afterdosing with either Compound B or Compound A using the previouslydescribed powder in capsule formulation. As is shown in Table 5, theAUC_(0-72 h) measured for Compound A in plasma was higher after dosingwith Compound B than the value measured after dosing with an equivalentdose of Compound A.

TABLE 5 Dose Compound AUC_(0-72h) (nM • h) Compound B Compound B BLQ(9.7 mg-eq/kg) Intermediate A BLQ Compound A 149000 Compound A CompoundA  65100 (9.7 mg/kg)

Compound C was dosed as 3 mg/mL solution to beagle dogs (N=3) using thefollowing formulation: 3 mg/kg Compound C₁₋₅% ethanol, 55% polyethyleneglycol 300, and 40% (5% dextrose in water). Samples were assessed forthe presence of Compound C, intermediate Compound D, and Compound A.FIG. 2 shows plasma concentrations of Compound A and Compound D (nM)during a 72 hour time period after dosing with Compound C using thepreviously described solution formulation. As can be seen in FIG. 2 andreported in Table 6, Compound C converted in vivo to both Compound D andCompound A in measurable amounts.

TABLE 6 Dose Species AUC_(0-72h) (nM • h) Compound C Compound C BLQ (3mg-eq/kg) Compound D  2984 Compound A 27360

1-54. (canceled)
 55. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 56. A compositioncomprising the compound according to claim 55 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 57.A method of treating a disease or condition selected from diversioncolitis, ischemic colitis, infectious colitis, chemical colitis,microscopic colitis, atypical colitis, pseudomembranous colitis,fulminant colitis, autistic enterocolitis, indeterminate colitis,Behcet's disease, gastroduodenal CD, jejunoileitis, ileitis,ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome,mucositis, radiation induced enteritis, short bowel syndrome, celiacdisease, stomach ulcers, diverticulitis, pouchitis, proctitis, chronicdiarrhea, Crohn's disease, and ulcerative colitis, in a human patient inneed thereof, comprising administering to the patient an effectiveamount of the composition of claim
 56. 58. A method of treatinginflammatory bowel disease in a human patient in need thereof,comprising administering to the patient an effective amount of thecomposition of claim
 56. 59. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 60. A compositioncomprising the compound according to claim 59 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 61.A method of treating a disease or condition selected from diversioncolitis, ischemic colitis, infectious colitis, chemical colitis,microscopic colitis, atypical colitis, pseudomembranous colitis,fulminant colitis, autistic enterocolitis, indeterminate colitis,Behcet's disease, gastroduodenal CD, jejunoileitis, ileitis,ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome,mucositis, radiation induced enteritis, short bowel syndrome, celiacdisease, stomach ulcers, diverticulitis, pouchitis, proctitis, chronicdiarrhea, Crohn's disease, and ulcerative colitis, in a human patient inneed thereof, comprising administering to the patient an effectiveamount of the composition of claim
 60. 62. A method of treatinginflammatory bowel disease in a human patient in need thereof,comprising administering to the patient an effective amount of thecomposition of claim
 60. 63. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 64. A compositioncomprising the compound according to claim 63 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 65.A method of treating a disease or condition selected from diversioncolitis, ischemic colitis, infectious colitis, chemical colitis,microscopic colitis, atypical colitis, pseudomembranous colitis,fulminant colitis, autistic enterocolitis, indeterminate colitis,Behcet's disease, gastroduodenal CD, jejunoileitis, ileitis,ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome,mucositis, radiation induced enteritis, short bowel syndrome, celiacdisease, stomach ulcers, diverticulitis, pouchitis, proctitis, chronicdiarrhea, Crohn's disease, and ulcerative colitis, in a human patient inneed thereof, comprising administering to the patient an effectiveamount of the composition of claim
 64. 66. A method of treatinginflammatory bowel disease in a human patient in need thereof,comprising administering to the patient an effective amount of thecomposition of claim
 64. 67. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 68. A compositioncomprising the compound according to claim 67 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 69.A method of treating a disease or condition selected from diversioncolitis, ischemic colitis, infectious colitis, chemical colitis,microscopic colitis, atypical colitis, pseudomembranous colitis,fulminant colitis, autistic enterocolitis, indeterminate colitis,Behcet's disease, gastroduodenal CD, jejunoileitis, ileitis,ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome,mucositis, radiation induced enteritis, short bowel syndrome, celiacdisease, stomach ulcers, diverticulitis, pouchitis, proctitis, chronicdiarrhea, Crohn's disease, and ulcerative colitis, in a human patient inneed thereof, comprising administering to the patient an effectiveamount of the composition of claim
 68. 70. A method of treatinginflammatory bowel disease in a human patient in need thereof,comprising administering to the patient an effective amount of thecomposition of claim 68.